CN102241648A - Multimedicine-resistance medicine-resistance taxane derivatives and preparation method and use thereof - Google Patents

Multimedicine-resistance medicine-resistance taxane derivatives and preparation method and use thereof Download PDF

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CN102241648A
CN102241648A CN201110127602XA CN201110127602A CN102241648A CN 102241648 A CN102241648 A CN 102241648A CN 201110127602X A CN201110127602X A CN 201110127602XA CN 201110127602 A CN201110127602 A CN 201110127602A CN 102241648 A CN102241648 A CN 102241648A
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alkyl
general formula
taxane derivatives
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side chain
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CN102241648B (en
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李英霞
耿美玉
王军飞
刘红椿
丁宁
张伟
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Shenyang Xinkang Pharmaceutical Research Co., Ltd
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Fudan University
Shanghai Institute of Materia Medica of CAS
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Abstract

The invention relates to taxane derivatives of a structural formula (I) and a preparation method and use thereof. In the structural formula (1), R1 represents -C(O)OR6, -C(O)Ar and -C(O)CH=CR7R8, such as -C(O)CH=CF2, -C(O)CH=C(CH)2, -C(O)CH=CHCH3 and -C(O)CH=CHCF3; R2 represents -Ar, alkyl and -CH=CR7R8, such as -CH-CF2, -CH=C(CH3)2 and -CH2CH(CH3)2; R3 represents hydrogen, alkyl, alkoxy, halo, cyano, azido, fluorinated alkyl and fluorinated alkoxy, such as methyl, chlorine atom, fluorine atom and trifluoromethyl; R4 represents hydrogen atom, -C(O)R9 and water solubility increasing hydroxy substituents; R5 represents hydrogen atom, silo ester, water solubility increasing hydroxy substituents, R6 represents C3 to C10 straight chain or branched alkyl; R7 and R8 represent identical or different C1 to C10 straight chain or branched alkyl, cycloalkyl, halo, halogenated C1 to C10 straight chain or branched alkyl or cycloalkyl; and R9 represents C1 to C10 straight chain or branched alkyl or cycloalkyl. Most of these compounds can effectively suppress the growth of tumor cells and can be used for treating multimedicine-resistance and medicine-resistance tumors in which P-glycoprotein is highly expressed.

Description

Anti-multidrug resistance taxane derivatives and its production and application
Technical field
The present invention relates to novel anti-multidrug resistance (MDR) taxane derivatives of a class in the synthetic field of medicine and its production and application, specifically a class can suppress the compound of growth of tumour cell effectively, especially at highly drug-fast MDR tumour cell (MCF-7/ADR, KB/VCR), with taxol (Paclitaxel, Taxol) compare and have 3 ~ 5 active raisings of the order of magnitude, with Docetaxel (Docetaxel, Taxotere) compare and have 1 ~ 3 active raising of the order of magnitude, with La Luotasai (Larotaxel, XRP9881) compare and have 1 ~ 2 active raising of the order of magnitude, this taxane derivatives can be used for clinically multidrug resistance tumor treatment and the exploitation to high expression level P-glycoprotein.
Background technology
Cancer has become one of disease of serious harm human health, has become the second largest deadly cause of disease that is only second to cardiovascular and cerebrovascular diseases in China.
Taxol (Paclitaxel) and its semi-synthetic analogue Docetaxel (Docetaxel) are human up to now the most effectively one of cancer therapy drugs of finding, characteristics such as it has novel structure, anticancer mechanism uniqueness, anticancer effect is remarkable, anticancer spectrum is wide, continue the end of the year 1992 after U.S. listing, successively go through to go on the market in more than 40 countries, and being widely used in the treatment of mammary cancer, lung cancer, cancer of the stomach, esophagus cancer, ovarian cancer etc. as a line cancer therapy drug, its anticancer effect is apparently higher than conventional cancer therapy drugs such as Zorubicin, Fluracil, cis-platinums.
Yet the same with other chemotherapeutics although they have significant anticancer therapeutic, taxol and Docetaxel are for MDR tumour non-activity almost, and this also is the major reason that the taxol medication causes the chemotherapy failure.Taxol and Docetaxel can not be oral and can't be seen through hemato encephalic barrier (BBB), have also limited the phase clinical application.Thereby development has better bioavailability, antitumour activity is better than taxol, and especially still keep the taxanes cancer therapy drug of anticancer therapeutic for the multidrug resistance tumour of high expression level P-glycoprotein is domestic and international pharmaceutical science man's research focus always.
Figure 201110127602X100002DEST_PATH_IMAGE001
Summary of the invention
The preparation method and the application thereof of novel anti-multidrug resistance (MDR) taxane derivatives have been an object of the present invention is to provide;
Another object of the present invention has provided a class and has had the taxane derivatives shown in the following general formula (I):
Figure DEST_PATH_GDA0000067832540000022
In the general formula: R 1Representative-C (O) OR 6,-C (O) Ar ,-C (O) CH=CR 7R 8, R wherein 6Represent C 3～C 10The alkyl of straight or branched, R 7, R 8Represent identical or different C 1～C 10Straight chain or have the C that the alkyl, cycloalkyl, halogen, halogen of side chain replace 1～C 10Straight chain or have the alkyl or cycloalkyl of side chain, R 1For example be-C (O) CH=CF 2,-C (O) OCCH 3,-C (O) CH=C (CH 3) 2,-C (O) CH=CHCH 3,-C (O) CH=CHCF 3Deng; R 2Representative-Ar, C 1～C 10Straight chain or have side chain alkyl ,-CH=CR 7R 8, R wherein 7, R 8When replacing for halogen, halogen is fluorine, chlorine, bromine, iodine, R 2For example be-CH=CF 2,-CH=CHCF 3Deng; R 3Represent hydrogen atom, alkyl, alkoxyl group, halogen, cyano group, azido-, fluorine substituted alkyl, fluorine substituted alkoxy etc., wherein, R 3When replacing for halogen, described halogen is fluorine, chlorine, bromine, iodine; Described fluorine substituted alkyl is :-CF 3,-CHF 2,-CF 2CF 3Deng; Described fluorine substituted alkyl is :-OCF 3,-OCHF 2,-OCF 2CF 3Deng; R 4Represent hydrogen atom ,-C (O) R 9Maybe can increase water miscible hydroxyl substituent etc., wherein, R 9Represent C 1～C 10Straight chain or have alkyl or cycloalkyl, aryl of side chain etc.; R 5Represent hydrogen atom, silicon ether, ester group maybe can increase water miscible hydroxyl substituent.Wherein, described can the water miscible hydroxyl substituent of increase be C 5～C 12Various carbohydrate or-CO-X-Y, wherein X representative-(CH 2) n-(n=1～6) or-CH=CH-; Y representation carboxy and pharmaceutically acceptable various salt thereof (for example: carboxylic acid sodium salt, carboxylic acid ammonia salt etc.), sulfonic group and pharmaceutically acceptable various salt thereof ,-N R 10R 11And pharmaceutically acceptable various salt (for example: front three amine salt, triethylamine salt etc.), C 5～C 12Various carbohydrate (for example: glucose, semi-lactosi etc.), wherein, R 10, R 11Represent identical or different C 1～C 10Straight chain or have alkyl, cycloalkyl of side chain etc., X and Y also can represent C 5～C 12Various carbohydrate (for example: glucose, semi-lactosi etc.);
The purpose of this invention is to provide taxane derivatives with following structural formula:
Figure DEST_PATH_GDA0000067832540000031
Compound number R 1 R 2 R 3 R 4
I-1a Tertbutyloxycarbonyl Phenyl Methyl Ethanoyl
I-1b Tertbutyloxycarbonyl Phenyl Methoxyl group Ethanoyl
I-1c Tertbutyloxycarbonyl Phenyl Trifluoromethyl Ethanoyl
I-1d Tertbutyloxycarbonyl Phenyl Trifluoromethoxy Ethanoyl
I-1e Tertbutyloxycarbonyl Phenyl Fluorine atom Ethanoyl
I-1f Tertbutyloxycarbonyl Phenyl The chlorine atom Ethanoyl
I-1g Tertbutyloxycarbonyl Phenyl Cyano group Ethanoyl
I-1h Tertbutyloxycarbonyl Phenyl Azido- Ethanoyl
I-2a Tertbutyloxycarbonyl 2,2-difluoroethylene base Hydrogen atom Ethanoyl
I-2b Tertbutyloxycarbonyl 2-methyl isophthalic acid-propenyl Hydrogen atom Ethanoyl
I-2c Tertbutyloxycarbonyl Isobutyl- Hydrogen atom Ethanoyl
I-3a (E)-2-methyl-2-butene acyl group 2-methyl isophthalic acid-propenyl Hydrogen atom Ethanoyl
I-3b (E)-the 2-butylene acyl group 2-methyl isophthalic acid-propenyl Hydrogen atom Ethanoyl
I-3c 3,3 '-the dimethyl propylene enoyl- 2-methyl isophthalic acid-propenyl Hydrogen atom Ethanoyl
I-3d (E)-2-methyl-2-butene acyl group Isobutyl- Hydrogen atom Ethanoyl
I-3e (E)-the 2-butylene acyl group Isobutyl- Hydrogen atom Ethanoyl
I-3f 3,3 '-the dimethyl propylene enoyl- Isobutyl- Hydrogen atom Ethanoyl
I-4a Tertbutyloxycarbonyl Phenyl Hydrogen atom Methyl
I-4b Tertbutyloxycarbonyl Phenyl Hydrogen atom Hydroxyl
I-5a Tertbutyloxycarbonyl 2,2-difluoroethylene base Azido- Ethanoyl
I-5b (E)-the 2-butylene acyl group 2,2-difluoroethylene base Hydrogen atom Ethanoyl
I-5c (E)-the 2-butylene acyl group 2,2-difluoroethylene base Azido- Ethanoyl
I-5d (E)-4,4,4-three fluoro-2-butylene acyl groups 2,2-difluoroethylene base Hydrogen atom Ethanoyl
I-5e (E)-4,4,4-three fluoro-2-butylene acyl groups 2,2-difluoroethylene base Azido- Ethanoyl
Taxane derivatives shown in the above-mentioned general formula (I) can prepare with for example following method, but preparation method of the present invention is not limited to these methods:
With the compound shown in the following general formula (II):
Figure DEST_PATH_GDA0000067832540000041
React with the compound shown in following general formula (III-1), (III-2), (III-3), (III-4):
Wherein, R 2, R 3, R 4, R 5, R 6, R 7, R 8Definition identical with claim 1 and 2.As reacting with general formula (III-1), used alkali comprises organic bases, as: triethylamine, pyridine, N, N-diisopropylethylamine, 4-Dimethylamino pyridine etc., or mineral alkali, as: yellow soda ash, salt of wormwood, sodium bicarbonate etc.Solvent can be any solvent of reacting of self not participating in, as: methylene dichloride, acetonitrile, DMF, toluene, ethyl acetate, ether, tetrahydrofuran (THF), pyridine etc., temperature of reaction can be carried out between ice bath is down to 200 ℃; As reacting with general formula (III-3), used condensing agent can be any condensing agent that can form amido linkage, as is dicyclohexylcarbodiimide (DCC), DIC carbodiimides such as (DIC) type condensing agent or thionyl chloride, oxalyl chloride etc.Used alkali comprises organic bases, as: triethylamine, pyridine, N, N-diisopropylethylamine, 4-Dimethylamino pyridine (DMAP) etc., or mineral alkali, as: yellow soda ash, salt of wormwood, sodium bicarbonate etc.Solvent can be any solvent of reacting of self not participating in, as: methylene dichloride, acetonitrile, DMF, toluene, ethyl acetate, ether, tetrahydrofuran (THF), pyridine etc., temperature of reaction can be carried out between ice bath is down to 200 ℃.
With obtain as general formula ( II) shown in compound remove R 5Protecting group can obtain general formula ( I) shown in taxane derivatives, R wherein 1, R 2, R 3, R 4, R 5, R 6, R 7, R 8Definition identical with claim 1 and 2.Wherein, when the hydroxyl protecting group of C-3 ' position is the silicon ether protective group, as: the silicon ether protecting group that tertiary butyl dimethyl silica-based (TBS), triethyl silica-based (TES), triisopropylsilyl (TIPS), trimethyl silicon based (TMS) or aryl replace etc., this moment protecting group to remove reagent be tetrabutyl ammonium fluoride, hydrogen fluoride/pyridine etc., solvent is any solvent of reacting of not participating in, as tetrahydrofuran (THF), ethyl acetate, ether, dioxane etc.; If when C-3 ' position hydroxyl protecting group methoxyl methyl (MOM), 1-ethoxyethyl group protecting groups such as (EE), it is various removal methods commonly used such as acetic acid/methyl alcohol that the protecting group of this moment removes reagent.
Midbody compound shown in the general formula (II) can dock by the compound shown in the logical formula V and various types of side chain precursors (beta-lactam, five yuan of oxazole ring carboxylic-acids, straight-chain carboxylic acid's class etc.), removes pendant hydroxyl group protecting group (R then 5) remove tertbutyloxycarbonyl (Boc) protecting group again and obtain, perhaps remove tertbutyloxycarbonyl earlier and take off the pendant hydroxyl group protecting group again and prepare:
For example: the compound shown in the general formula (II) can prepare (Scheme 1) by following reaction formula by logical formula V and beta-lactam type side chain general formula (VI-1):
Figure DEST_PATH_GDA0000067832540000061
Wherein, the used alkali of butt joint reaction can be hexamethyl two silica-based amido lithiums (LiHMDS), sodium hexamethyldisilazide (NaHMDS), sodium hydride (NaH) etc., and used solvent is tetrahydrofuran (THF), dioxane etc.Used temperature of reaction is between-60 ℃ to 25 ℃, and used beta-lactam intermediate equivalents is 1.2 to 2.0 equivalents (encircling intermediate V with respect to mother).The silicon ether protective group R5 of described beta-lactam C-3 position is the silicon ether protecting group of TBS, TES, TIPS, TMS or aryl replacement etc.The condition that intermediate has been reported with trifluoroacetic acid/dichloromethane or formic acid/methyl alcohol etc. shown in the general formula (II-1) that butt joint is obtained removes Boc and obtains compound shown in the general formula (II) under the ice bath, this moment R 2, R 3, R 4, R 5Definition identical with claim 1 and 2; Also can remove the pendant hydroxyl group protecting group (R of the intermediate shown in the general formula (II-1) earlier 5), remove Boc again and prepare compound shown in the general formula (II-3), at this moment R 2, R 3, R 4The same.
Compound shown in the logical formula V can be set out by raw material midbody (V-1), prepares (Scheme 2) by following reaction formula:
Figure DEST_PATH_GDA0000067832540000071
R in the formula 3, R 4Definition identical with claim 1 and 2.Midbody compound (V-2) can be obtained by oxidation C-13 position secondary hydroxyl by raw material (V-1), and used oxygenant can be the reagent of any oxidation secondary hydroxyl commonly used, as: PCC, PDC, ozone, Manganse Dioxide etc.Midbody compound (V-3) can remove the C-2 benzoyl by reported method by the intermediate (V-2) of preparation and obtain, as: Red-Al or the methods such as quaternary ammonium salt that some is alkaline.
General formula ( V-4) shown in compound can by general formula ( V-3) shown in intermediate by and phenylformic acid (1.0 eq ~ 30 eq) condensation that replaces of various positions obtain, used condensing agent is carbodiimide class condensing agent (1.0 eq ~ 30 eq), as: DCC, DIC etc., used catalyzer are DMAP etc.Solvent can be any solvent of reacting of self not participating in, as: methylene dichloride, acetonitrile, DMF, toluene, tetrahydrofuran (THF) etc., temperature of reaction can be carried out between ice bath is down to 200 ℃.
General formula ( V-5) shown in compound can by general formula ( V-4) shown in intermediate remove C-10 position ethanoyl protecting group by reported method and obtain, as hydrazine hydrate, hydrogen peroxide/sodium bicarbonate etc.General formula ( V-6) shown in compound can by intermediate ( V-5) obtain by acylations and alkylation.Wherein, acylations can by with general formula ( III-1), ( III-2), ( III-3)The intermediate reaction obtains, and used alkali comprises organic bases, as: triethylamine, pyridine, N, N-diisopropylethylamine, DMAP etc., or mineral alkali, as: yellow soda ash, salt of wormwood, sodium bicarbonate etc.Solvent can be any solvent of reacting of self not participating in, as: methylene dichloride, acetonitrile, DMF, toluene, ethyl acetate, ether, tetrahydrofuran (THF), pyridine etc., temperature of reaction can be carried out between ice bath is down to 200 ℃; Wherein, the 10-hydroxy alkylated can be by realizing that with various halohydrocarbons reactions alkali comprises LiHMDS, NaHMDS, NaH etc.Solvent can be any solvent of reacting of self not participating in, as: dioxane, DMF, tetrahydrofuran (THF) etc. can directly be solvent with the haloalkane perhaps, and temperature of reaction can be carried out between ice bath is down to 80 ℃.
General formula ( V) shown in compound can by general formula ( V-6) intermediate obtains by reduction C-13 position carbonyl, used reductive agent can be sodium borohydride, Raneynickel/H 2Deng, solvent can be tetrahydrofuran (THF), methyl alcohol, ethanol, ethyl acetate etc., temperature of reaction can be carried out between-10 ℃ to 50 ℃.
β -The lactams general formula ( VI-1-9), ( VI-1-10), ( VI-1-11) can obtain by following prepared in reaction ( Scheme 3):
Figure DEST_PATH_IMAGE009
Scheme?3
R in the formula 5, R 7, R 8Definition identical with claim 1 and 2.According to reported method, with the aldehyde that replaces with replace phenylamino under suitable dewatering agent effect, form the schiffbase general formula ( VI-1-1) compound, directly and the alpha-acyloxy acetyl halide ring-closure reaction takes place under organic base catalytic, obtain racemic beta-lactam intermediate general formula ( VI-1-2) compound, directly carry out saponification reaction obtain general formula ( VI-1-3) intermediate.Then carry out protections such as hydroxyl silicon etherificate or acylations, the gained general formula ( VI-1-4) compound oxidation removal beta-lactam amino protecting group under low temperature, obtain general formula ( VI-1-6) compound, then with Boc-acid anhydrides ((Boc) 2O), obtain under the effect of organic bases and catalyzer DMAP general formula ( VI-1-10) compound, by reduce two keys can obtain again general formula ( VI-1-11) compound.
With the gained general formula ( VI-1-4) compound by the two keys of ozone oxidation fracture obtain containing aldehyde radical general formula ( VI-1-5) compound, contain various substituent side chains such as halogen by the Wittig prepared in reaction, for example: with difluorodibromomethane reaction, obtain general formula ( VI-1-7) intermediate, then under lesser temps oxidation removal beta-lactam amino protecting group obtain general formula ( VI-1-8) compound, then with (Boc) 2Obtain under the effect of O, organic bases and catalyzer DMAP general formula ( VI-1-9) compound.
In addition, general formula ( I) R 4, R 5Hydroxyl substituent can be introduced suitable water soluble group, for example C 5~ C 12Various carbohydrate or-CO-X-Y, wherein X representative-(CH 2) n-(n=1 ~ 6) or-CH=CH-; Y representation carboxy and pharmaceutically acceptable various salt (for example: carboxylic acid sodium salt, carboxylic acid ammonia salt etc.), sulfonic group and pharmaceutically acceptable various salt ,-NR 10R 11With pharmaceutically acceptable various salt (for example: front three amine salt, triethylamine salt etc.), C 5~ C 12Various carbohydrate (for example: glucose, semi-lactosi etc.), wherein, R 10, R 11Represent identical or different C 1~ C 10Straight chain or have alkyl, cycloalkyl of side chain etc., X and Y also can represent C 5~ C 12Various carbohydrate (for example: glucose, semi-lactosi etc.).
  
Compound of the present invention can be used for preparing antitumor drug, for general formula ( I) shown in bearing taxanes, this compounds majority can suppress the growth of tumour cell effectively, especially at MDR tumour cell (MCF-7/ADR, KB/VCR), with taxol (Paclitaxel, Taxol) compare and have 3 ~ 5 active raisings of the order of magnitude, with Docetaxel (Docetaxel, Taxotere) compare and have 1 ~ 3 active raising of the order of magnitude, compare with La Luotasai (Larotaxel) and to have 1 ~ 2 active raising of the order of magnitude, this taxane derivatives can be used for clinically multidrug resistance tumor treatment and the exploitation to high expression level P-glycoprotein.
Embodiment
Followingly further specify the present invention, but the invention is not restricted to these examples with reference to reference example and embodiment.
The preparation of beta-lactam shown in (Scheme 4), according to document (Ojima I. et al., Chirality, 2000, 12,431-441; Ojima I.et al., Bioorg. Med. Chem. 2003, 11,2867-2888 etc.) and the synthetic method of report, the methacrylaldehyde that end is replaced and the aniline of replacement form schiffbase under the dewatering agent effect VI-1-1, not purified directly and the alpha-acyloxy acetyl halide cycloaddition reaction takes place under organic base catalytic obtains racemic beta-lactam intermediate VI-1-2, the not purified saponification reaction of directly carrying out obtains intermediate VI-1-3Crude product obtains highly purified compound by step recrystallization purifying processing VI-1-3, three step total recoverys are stabilized in about 70%, then it are carried out the protection of silicon etherificate, obtain compound with quantitative yield VI-1-4, need not directly oxidation removal beta-lactam amino protecting group under low temperature of purifying, after the rapid column chromatography purification process, obtain compound with good yield VI-1-6, then with (Boc) 2Carry out the protection of amino Boc under the effect of O, organic bases and catalyzer DMAP, with quantitative yield key intermediate VI-1-10
The preparation of halogenated beta-lactam can be according to document (Ojima I. et al., J. Nat. Prod. 2009,72,554 – 565 etc.) Bao Dao synthetic method is finished, with the intermediate of silicon ether protection VI-1-4Carry out the two keys of ozone oxidation fracture, obtain containing the beta-lactam intermediate of aldehyde radical with quantitative yield VI-1-5, carry out the Wittig reaction with dibromodifluoromethane/three (dimethylamino) phosphines (HMPA) or difluoro sodium chloroacetate/triphenylphosphine then, obtain the lactam nucleus that difluoro replaces VI-1-7, then oxidation removal beta-lactam amino protecting group obtains intermediate with yield preferably VI-1-8, then with (Boc) 2O), under the effect of organic bases and catalyzer DMAP, carry out the protection of amino Boc, with quantitative yield key intermediate VI-1-9
  
The preparation of novel taxane analog derivative can prepare with reference to following method, but the invention is not restricted to these embodiment:
Agents useful for same: 4-Dimethylamino pyridine (DMAP), TERT-BUTYL DIMETHYL CHLORO SILANE (TBSCl), trifluoromethanesulfanhydride anhydride (Tf 2O), tetrabutyl ammonium fluoride (TBAF), ceric ammonium nitrate (CAN) etc. be the commercial reagent, is directly used in reaction.10-goes acetyl crust Ka Ting (10-DAB) to buy from Xi'an sky pavilion bio tech ltd.Used sherwood oil is 60 ~ 90 oThe C boiling range.Without specified otherwise, other is common homemade analytical reagent.CH wherein 2Cl 2Through CaH 2Reflux heavily to steam and handle, tetrahydrofuran (THF) (THF) is reformed through the sodium silk and is handled, and DMF, pyridine, acetonitrile, MeOH heavily steam after 3 molecular sieves are handled.
With thin-layer chromatography (TLC) detection reaction process, used thin plate is that Yantai chemical industry institute produces thin-layer chromatography silica gel precoated plate (silica gel granularity 10 ~ 40 M).The ultraviolet detection wavelength is 254 nm; With 5% aubepine-5% vitriol oil-1% Glacial acetic acid-ethanolic soln heating colour developing.The column chromatography used silica gel is available from subsidiary factory of Haiyang Chemical Plant, Qingdao, and specification is 100 ~ 200 orders, 200 ~ 300 and 300 ~ 400 orders.
Bioexperiment material: KB, KB/VCR, four kinds of cell strains of MCF-7, MCF-7/ADR are Shanghai medicine institute of Chinese Academy of Sciences pharmacological evaluation chamber and provide; Sodium.alpha.-ketopropionate, glutamine, sulphonyl rhodamine B (sulforhodamin B, SRB), dimethyl sulfoxide (DMSO) (DMSO) (being U.S. Sigma company product); Calf serum (FBS), DMEM substratum, MEM culture medium dry powder and trypsin are U.S. GIBCO company product); Other reagent such as trichoroacetic acid(TCA), acetic acid are analytical pure (Chemical Reagent Co., Ltd., Sinopharm Group); Water is injection physiological saline.
Main laboratory apparatus: nuclear magnetic resonance spectrometer (JEOL-ECP-600, interior mark: TMS, DSS), Fourier transformation infrared spectrometer (Nicolet Nexus-470), the part nuclear magnetic data is from Qingdao Haiyang 500 MHz of the Chinese Academy of Sciences, pharmaceutical college of Fudan University 400 MHz nuclear magnetic resonance spectrometers.Cell counter (Beckman 6605698), photoabsorption microplate reader (MY190).
  
13-carbonyl-7-deoxidation-7 β, 8 β-methylene radical-baccatin III (V-2):
With compound 7-deoxidation-7 β, 8 β-methylene radical-baccatin III ( V-1) (2.8 g, 5.0 mmol) be dissolved in the exsiccant methylene dichloride (120 mL), add pyridinium dichromate (PDC) (2.2 g under the room temperature, 6.0 mmol) with 4 molecular sieves (6.0 g), react 3 h, after TLC detects no raw material residue, with the mixture suction filtration, and use ethyl acetate drip washing for several times repeatedly, organic layer is collected, use 1 M hydrochloric acid (100 mL * 3) successively, saturated sodium bicarbonate aqueous solution (50 mL * 3), saturated sodium-chloride water solution (50 mL * 3) washing, anhydrous sodium sulfate drying, concentrate and obtain the reddish-brown solid, obtain white powder solid 13-carbonyl-7-deoxidation-7 β with recrystallization from ethyl acetate/petroleum ether, 8 β-methylene radical-baccatin III ( V-2) (2.8 g, 96% yield): 1H NMR (400 MHz, CDCl 3) δ 8.09 (d, J=7.8 Hz, 2 H, Ph-H), 7.64 (t, J=7.4 Hz, 1 H, Ph-H), 7.50 (t, J=7.8 Hz, 2 H, Ph-H), 6.42 (s, 1 H, H-10), 5.73 (d, J=7.8 Hz, 1 H, H-2), 4.72 (d, J=3.9 Hz, 1 H, H-5), 4.31 (d, J=8.6 Hz, 1 H, H-20a), 4.19 (d, J=7.4 Hz, 1 H, H-3), 4.00 (d, J=8.6 Hz, 1 H, H-20b), 3.06 (d, J=20.0 Hz, 1 H, H-14a), 2.68 (d, J=20.0 Hz, 1 H, H-14b), 2.45 (dt, J=16.4,4.3 Hz, 1 H, H-6a), 2.25 (s, 3 H, C H 3CO in C-10), and 2.20-2.31 (m, 1 H, H-19a), 2.13 (s, 3 H, C H 3CO in C-4), 2.04-2.12 (m, 1 H, H-6b), 2.02 (s, 3 H, H-18), 1.63-1.67 (m, 1 H, H-19b), 1.34 (m, 1 H, H-7), 1.29 (s, 3 H, H-16), 1.26 (s, 3 H, H-17).
Remove benzoyl-13-carbonyl-7-deoxidation-7 β, 8 β-methylene radical-baccatin III (V-3):
With compound 13-carbonyl-7-deoxidation-7 β, 8 β-methylene radical-baccatin III ( V-2) (1.1 g; 2.0 mmol) be dissolved in tetrahydrofuran (THF) (30 mL); add tetrabutyl ammonium fluoride (1.6 g; 6.0 mmol); stirring at room 6 h; after TLC detects no raw material residue; reaction solution is concentrated; gains dilute with ethyl acetate (150 mL); use 1 M hydrochloric acid (100 mL * 3) successively; saturated sodium bicarbonate aqueous solution (50 mL * 3); saturated sodium-chloride water solution (50 mL * 3) washing, anhydrous sodium sulfate drying concentrates and obtains the reddish-brown solid; crude product obtains orange/yellow solid 2-through column chromatography for separation (petrol ether/ethyl acetate=1/1) and removes benzoyl-13-carbonyl-7-deoxidation-7 β, 8 β-methylene radical-baccatin III ( V-3) (672.7 mg, 80% yield): 1H NMR (400 MHz, CDCl 3) δ 6.36 (s, 1 H, H-10), 4.73 (d, J=3.5 Hz, 1 H, H-5), 4.59 (d, J=9.4 Hz, 1 H, H-20a), 4.50 (d, J=9.8 Hz, 1 H, H-20b), 4.08 (d, J=7.4 Hz, 1 H, H-3), 3.74 (d, J=7.4 Hz, 1 H, H-2), 2.91 (d, J=19.6 Hz, 1 H H-14a), 2.61 (dd, J=19.6,1.2 Hz, 1 H, H-14b), 2.43 (dt, J=16.4,4.3 Hz, 1 H, H-6a), 2.22 (s, 3 H, C H 3CO in C-4), 2.18 (dd, J=9.8,5.5 Hz, 1 H, H-19a), 2.11 (broad d, J=16.0 Hz, 1 H, H-6b), 1.98 (s, 3 H, C H 3CO in C-10), 1.94 (s, 3 H, H-18), 1.71-1.75 (m, 1 H, H-19b), 1.29-1.33 (m, 1 H, H-7), 1.26 (s, 3 H, H-16), 1.19 (s, 3 H, H-17).
Remove benzoyl-2-(m-trifluoromethyl benzoyl)-13-carbonyl-7-deoxidation-7 β, 8 β-methylene radical-baccatin III (V-4a):
The intermediate 2-of preparation is removed benzoyl-13-carbonyl-7-deoxidation-7 β, 8 β-methylene radical-baccatin III ( V-3) (84.0 mg; 0.2 mmol); m-trifluoromethyl phenylformic acid (304.2 mg; 1.0 mmol); and DMAP (24.4 mg; 0.2 mmol) be dissolved in methylene dichloride (20 mL); add condensing agent dicyclohexylcarbodiimide (DCC) (330.1 mg; 1.6 mmol); stir 48 h. down with the reaction solution suction filtration in 40 ° of C; organic layer dilutes with methylene dichloride; use 1 M hydrochloric acid (10 mL * 3) successively; saturated sodium bicarbonate aqueous solution (10 mL * 3); saturated sodium-chloride water solution (10 mL * 3) washing, anhydrous sodium sulfate drying concentrates and obtains white solid; crude product obtains white powder solid 2-through column chromatography for separation (petrol ether/ethyl acetate=1/1) and removes benzoyl-2-(m-trifluoromethyl benzoyl)-13-carbonyl-7-deoxidation-7 β, 8 β-methylene radical-baccatin III ( V-4a) (115.8 mg, 91%): 1H NMR (400 MHz, CDCl 3) δ 8.42 (s, 1 H, Ph-H), 8.28 (d, J=7.8 Hz, 1 H, Ph-H), 7.90 (d, J=7.8 Hz, 1 H, Ph-H), 7.67 (t, J=7.8 Hz, 1 H, Ph-H), 6.43 (s, 1 H, H-10), 5.71 (d, J=7.4 Hz, 1 H, H-2), 4.75 (d, J=3.9 Hz, 1 H, H-5), 4.26 (d, J=8.6 Hz, 1 H, H-20a), 4.22 (d, J=7.8 Hz, 1 H, H-3), 4.00 (d, J=8.6 Hz, 1 H, H-20b), 3.00 (d, J=20.0 Hz, 1 H, H-14a), 2.69 (d, J=20.0 Hz, 1 H, H-14b), 2.46 (dt, J=16.0,3.9 Hz, 1 H, H-6a), 2.30 (dd, J=10.2,5.1 Hz, 1 H, H-19a), 2.26 (s, 3 H, C H 3CO in C-10), 2.13 (s, 3 H, C H 3CO in C-4), 2.09 (broad s, 1 H, H-6b), 2.03 (s, 3 H, H-18), 1.67 (t like, J=6.7 Hz, 1 H, H-19b), 1.35 (m, 1 H, H-7), 1.30 (s, 3 H, H-16), 1.25 (s, 3 H, H-17).
According to identical method can prepare other the substituted intermediate of C-2 benzoyl ( V-4b ~ V-4h):
2-removes benzoyl-2-(-methyl benzoyl)-13-carbonyl-7-deoxidation-7 β, and 8 β-methylene radical-baccatin III (V-4b): 1H NMR (400 MHz, CDCl 3) δ 7.88-7.92 (m, 2 H, Ph-H), 7.36-7.45 (m, 2 H, Ph-H), 6.42 (s, 1 H, H-10), 5.71 (d, J=7.8 Hz, 1 H, H-2), 4.73 (d, J=3.5 Hz, 1 H, H-5), 4.31 (d, J=8.6 Hz, 1 H, H-20a), 4.19 (d, J=7.4 Hz, 1 H, H-3), 3.99 (d, J=9.0 Hz, 1 H, H-20b), 3.06 (d, J=20.0 Hz, 1 H, H-14a), 2.69 (d, J=20.0 Hz, 1 H, H-14b), 2.41-2.47 (m, 4 H, H-6a and PhC H 3), 2.27-2.31 (m, 1 H, H-19a), 2.25 (s, 3 H, C H 3CO in C-10), 2.13 (s, 3 H, C H 3CO in C-4), 2.08 (broad s, 1 H, H-6b), 2.03 (s, 3 H, H-18), 1.66 (t like, J=6.3 Hz, 1 H, H-19b), 1.33 (m, 1 H, H-7), 1.30 (s, 3 H, H-16), 1.25 (s, 3 H, H-17).
Remove benzoyl-2-(-anisoyl)-13-carbonyl-7-deoxidation-7 β, and 8 β-methylene radical-baccatin III (V-4c): 1H NMR (400 MHz, CDCl 3) δ 7.70 (d, J=7.8 Hz, 1 H, Ph-H), 7.62 (s, 1 H, Ph-H), 7.40 (t, J=8.2 Hz, 1 H, Ph-H), 7.17 (d, J=8.2 Hz, 1 H, Ph-H), 6.43 (s, 1 H, H-10), 5.73 (d, J=7.4 Hz, 1 H, H-2), 4.73 (d, J=3.5 Hz, 1 H, H-5), 4.35 (d, J=8.6 Hz, 1 H, H-20a), 4.20 (d, J=7.4 Hz, 1 H, H-3), 4.00 (d, J=8.6 Hz, 1 H, H-20b), 3.87 (s, 3 H, OC H 3), 3.05 (d, J=20.0 Hz, 1 H, H-14a), 2.69 (d, J=20.0 Hz, 1 H, H-14b), 2.46 (dt, J=16.0,4.3 Hz, 1 H, H-6a), 2.23-2.31 (m, J=10.2,5.1 Hz, 1 H, H-19a), 2.26 (s, 3 H, C H 3CO in C-10), 2.12 (s, 3 H, C H 3CO in C-4), 2.08-2.13 (m, 1 H, H-6b), 2.03 (s, 3 H, H-18), 1.67 (t like, J=6.7 Hz, 1 H, H-19b), 1.28-1.33 (m, 1 H, H-7), 1.30 (s, 3 H, H-16), 1.25 (s, 3 H, H-17).
Remove benzoyl-2-(-trifluoromethoxy benzoyl)-13-carbonyl-7-deoxidation-7 β, and 8 β-methylene radical-baccatin III (V-4d): 1H NMR (400 MHz, CDCl 3) δ 8.04 (d, J=7.8 Hz, 1 H, Ph-H), 7.97 (s, 1 H, Ph-H), 7.54-7.58 (m, 1 H, Ph-H), 7.49 (t, J=7.8 Hz, 1 H, Ph-H), 6.43 (s, 1 H, H-10), 5.72 (d, J=7.8 Hz, 1 H, H-2), 4.74 (broad s, 1 H, H-5), 4.29 (d, J=8.2 Hz, 1 H, H-20a), 4.21 (d, J=7.8 Hz, 1 H, H-3), 3098 (d, J=8.2 Hz, 1 H, H-20b), 3.00 (d, J=20.0 Hz, 1 H, H-14a), 2.69 (d, J=20.0 Hz, 1 H, H-14b), 2.46 (dt, J=16.0,4.3 Hz, 1 H, H-6a), 2.28-2.30 (m, 1 H, H-19a), 2.26 (s, 3 H, C H 3CO in C-10), 2.12 (s, 3 H, C H 3CO in C-4), 2.09 (broad s, 1 H, H-6b), 2.03 (s, 3 H, H-18), 1.66 (t like, J=7.0 Hz, 1 H, H-19b), 1.35 (m, 1 H, H-7), 1.29 (s, 3 H, H-16), 1.25 (s, 3 H, H-17).
Remove benzoyl-2-(-fluoro benzoyl)-13-carbonyl-7-deoxidation-7 β, and 8 β-methylene radical-baccatin III (V-4e): 1H NMR (400 MHz, CDCl 3) δ 7.89 (d, J=7.8 Hz, 1 H, Ph-H), 7.78 (dd, J=9.0,1.5 Hz, 1 H, Ph-H), 7.46-7.52 (m, 1 H, Ph-H), 7.32-7.37 (m, 1 H, Ph-H), 6.43 (s, 1 H, H-10), 5.71 (d, J=7.4 Hz, 1 H, H-2), 4.74 (d, J=3.5 Hz, 1 H, H-5), 4.31 (d, J=8.6 Hz, 1 H, H-20a), 4.20 (d, J=7.8 Hz, 1 H, H-3), 3.99 (d, J=8.6 Hz, 1 H, H-20b), 3.02 (d, J=20.0 Hz, 1 H, H-14a), 2.69 (d, J=20.0 Hz, 1 H, H-14b), 2.46 (dt, J=16.0,4.3 Hz, 1 H, H-6a), 2.30 (dd, J=9.8,5.9 Hz, 1 H, H-19a), 2.25 (s, 3 H, C H 3CO in C-10), 2.14 (s, 3 H, C H 3CO in C-4), 2.09 (broad s, 1 H, H-6b), 2.03 (s, 3 H, H-18), 1.66 (t like, J=6.7 Hz, 1 H, H-19b), 1.35 (m, 1 H, H-7), 1.30 (s, 3 H, H-16), 1.25 (s, 3 H, H-17).
Remove benzoyl-2-(-chlorobenzene formacyl)-13-carbonyl-7-deoxidation-7 β, and 8 β-methylene radical-baccatin III (V-4f): 1H NMR (400 MHz, CDCl 3) δ 8.10 (s, 1 H, Ph-H), 7.98 (d, J=7.8 Hz, 1 H, Ph-H), 7.61 (d, J=7.8 Hz, 1 H, Ph-H), 7.45 (t, J=7.8 Hz, 1 H, Ph-H), 6.42 (s, 1 H, H-10), 5.69 (d, J=7.4 Hz, 1 H, H-2), 4.74 (d, J=3.9 Hz, 1 H, H-5), 4.30 (d, J=8.6 Hz, 1 H, H-20a), 4.21 (d, J=7.4 Hz, 1 H, H-3), 3.98 (d, J=8.6 Hz, 1 H, H-20b), 3.02 (d, J=20.0 Hz, 1 H, H-14a), 2.69 (d, J=20.3 Hz, 1 H, H-14b), 2.45 (dt, J=16.0,5.1 Hz, 1 H, H-6a), 2.29 (dd, J=10.2,5.1 Hz, 1 H, H-19a), 2.26 (s, 3 H, C H 3CO in C-10), 2.15 (s, 3 H, C H 3CO in C-4), 2.11 (broad s, 1 H, H-6b), 2.03 (s, 3 H, H-18), 1.66 (t like, J=6.7 Hz, 1 H, H-19b), 1.34 (m, 1 H, H-7), 1.29 (s, 3 H, H-16), 1.25 (s, 3 H, H-17).
Remove benzoyl-2-(-cyano group benzoyl)-13-carbonyl-7-deoxidation-7 β, and 8 β-methylene radical-baccatin III (V-4g): 1H NMR (400 MHz, CDCl 3) δ 8.40 (s, 1 H, Ph-H), 8.31 (d, J=7.8 Hz, 1 H, Ph-H), 7.92 (d, J=7.4 Hz, 1 H, Ph-H), 7.67 (t, J=7.8 Hz, 1 H, Ph-H), 6.43 (s, 1 H, H-10), 5.71 (d, J=7.4 Hz, 1 H, H-2), 4.74 (d, J=3.5 Hz, 1 H, H-5), 4.24 (d, J=8.6 Hz, 1 H, H-20a), 4.22 (d, J=7.8 Hz, 1 H, H-3), 3.98 (d, J=8.6 Hz, 1 H, H-20b), 2.99 (d, J=20.0 Hz, 1 H, H-14a), 2.69 (d, J=20.0 Hz, 1 H, H-14b), 2.46 (dt, J=16.0,4.3 Hz, 1 H, H-6a), 2.30 (dd, J=10.6,5.1 Hz, 1 H, H-19a), 2.26 (s, 3 H, C H 3CO in C-10), 2.16 (s, 3 H, C H 3CO in C-4), 2.12 (d, J=16.0 Hz, 1 H, H-6b), 2.03 (s, 3 H, H-18), 1.66 (t like, J=6.7 Hz, 1 H, H-19b), 1.34 (m, 1 H, H-7), 1.30 (s, 3 H, H-16), 1.25 (s, 3 H, H-17).
Remove benzoyl-2-(-triazobenzene formyl radical)-13-carbonyl-7-deoxidation-7 β, and 8 β-methylene radical-baccatin III (V-4h): 1H NMR (400 MHz, CDCl 3) δ 7.87 (d, J=7.8 Hz, 1 H, Ph-H), 7.77 (s, 1 H, Ph-H), 7.49 (t, J=8.2 Hz, 1 H, Ph-H), 7.28 (d, J=8.2 Hz, 1 H, Ph-H), 6.43 (s, 1 H, H-10), 5.73 (d, J=7.4 Hz, 1 H, H-2), 4.74 (d, J=3.9 Hz, 1 H, H-5), 4.32 (d, J=8.6 Hz, 1 H, H-20a), 4.21 (d, J=7.4 Hz, 1 H, H-3), 3.99 (d, J=8.6 Hz, 1 H, H-20b), 3.02 (d, J=20.0 Hz, 1 H, H-14a), 2.69 (d, J=20.0 Hz, 1 H, H-14b), 2.46 (dt, J=16.4 Hz, 1 H, H-6a), 2.28-2.32 (m, 1 H, H-19a), 2.26 (s, 3 H, C H 3CO in C-10), 2.14 (s, 3 H, C H 3CO in C-4), 2.09 (broad s, 1 H, H-6b), 2.03 (s, 3 H, H-18), 1.66 (t like, J=6.7 Hz, 1 H, H-19b), 1.35 (m, 1 H, H-7), 1.30 (s, 3 H, H-16), 1.25 (s, 3 H, H-17).
Remove benzoyl-2-(m-trifluoromethyl benzoyl)-7-deoxidation-7 β, 8 β-methylene radical-baccatin III (V-5a):
The intermediate 2-of preparation is removed benzoyl-2-(m-trifluoromethyl benzoyl)-13-carbonyl-7-deoxidation-7 β, 8 β-methylene radical-baccatin III ( V-4a) (102.0 mg; 0.16 mmol) be dissolved in methyl alcohol (2 mL) and tetrahydrofuran (THF) (10 mL); ice bath adds sodium borohydride (121.1 mg down; 3.2 mmol); behind room temperature reaction 5 h; add saturated ammonium chloride (10 mL) termination reaction; mixture is extracted with ethyl acetate (30 mL * 3); merge organic phase; use 1 M hydrochloric acid (10 mL * 3) successively; saturated sodium bicarbonate aqueous solution (10 mL * 3); saturated sodium-chloride water solution (10 mL * 3) washing; anhydrous sodium sulfate drying; concentrate and obtain white solid; crude product obtains white powder solid 2-through column chromatography for separation (petrol ether/ethyl acetate=2/1) and removes benzoyl-2-(m-trifluoromethyl benzoyl)-7-deoxidation-7 β, 8 β-methylene radical-baccatin III ( V-5a) (100.2 mg, 98% yield): 1H NMR (400 MHz, CDCl 3) δ 8.47 (s, 1 H, Ph-H), 8.31 (d, J=7.8 Hz, 1 H, Ph-H), 7.88 (d, J=7.4 Hz, 1 H, Ph-H), 7.65 (t, J=7.8 Hz, 1 H, Ph-H), 6.35 (s, 1 H, H-10), 5.61 (d, J=7.8 Hz, 1 H, H-2), 4.83 (t, J=7.4 Hz, 1 H, H-13), 4.77 (d, J=3.5 Hz, 1 H, H-5), 4.25 (d, J=8.2 Hz, 1 H, H-20a), 4.20 (d, J=7.4 Hz, 1 H, H-3), 4.02 (d, J=8.2 Hz, 1 H, H-20b), 2.48 (dt, J=16.4,4.3 Hz, 1 H, H-6a), 2.23-2.35 (m, 3 H, H-14 and H-19a), 2.25 (s, 3 H, C H 3CO in C-10), 2.21 (s, 3 H, C H 3CO in C-4), 2.10 (d, J=16.0 Hz, 1 H, H-6b), 2.03 (s, 3 H, H-18), 1.63-1.67 (m, 1 H, H-19b), 1.35 (m, 1 H, H-7), 1.22 (s, 3 H, H-16), 1.10 (s, 3 H, H-17).
According to identical method can prepare other the substituted intermediate of C-2 benzoyl ( V-5b ~ V-5h):
2-removes benzoyl-2-(-methyl benzoyl)-7-deoxidation-7 β, and 8 β-methylene radical-baccatin III (V-5b): 1H NMR (400 MHz, CDCl 3) δ 7.93-7.97 (m, 2 H, Ph-H), 7.43 (d, J=7.8 Hz, 1 H, Ph-H), 7.37 (t, J=7.3 Hz, 1 H, Ph-H), 6.35 (s, 1 H, H-10), 5.61 (d, J=7.8 Hz, 1 H, H-2), 4.84 (t, J=7.8 Hz, 1 H, H-13), 4.76 (d, J=3.4 Hz, 1 H, H-5), 4.32 (d, J=8.8 Hz, 1 H, H-20a), 4.18 (d, J=7.8 Hz, 1 H, H-3), 4.03 (d, J=8.8 Hz, 1 H, H-20b), 2.48 (dt, J=16.1 Hz, 1 H, H-6a), 2.23-2.35 (m, 3 H, H-19a), 2.44 (s, 3 H, PhC H 3), 2.27 (s, 3 H, C H 3CO in C-10), and 2.23-2.38 (m, 2 H, H-14), 2.22 (s, 3 H, C H 3CO in C-4), 2.10 (d, J=15.6 Hz, 1 H, H-6b), 2.03 (s, 3 H, H-18), 1.65 (t like, 1 H, H-19b), 1.34 (m, 1 H, H-7), 1.23 (s, 3 H, H-16), 1.10 (s, 3 H, H-17).
Remove benzoyl-2-(-anisoyl)-7-deoxidation-7 β, and 8 β-methylene radical-baccatin III (V-5c): 1H NMR (400 MHz, CDCl 3) δ 7.73 (d, J=7.8 Hz, 1 H, Ph-H), 7.66 (d, J=2.7 Hz, 1 H, Ph-H), 7.39 (t, J=7.8 Hz, 1 H, Ph-H), 7.15 (dd, J=8.2,2.0 Hz, 1 H, Ph-H), 6.34 (s, 1 H, H-10), 5.62 (d, J=7.8 Hz, 1 H, H-2), 4.83 (t, J=7.4 Hz, 1 H, H-13), 4.75 (d, J=3.5 Hz, 1 H, H-5), 4.34 (d, J=8.6 Hz, 1 H, H-20a), 4.18 (d, J=7.8 Hz, 1 H, H-3), 4.03 (d, J=8.6 Hz, 1 H, H-20b), 3.87 (s, 3 H, OC H 3), 2.48 (dt, J=16.0,4.3 Hz, 1 H, H-6a), (2.23-2.37 m, 3 H, H-14 and H-19a), 2.25,2.20,2.09 (dd, J=16.0,6.3 Hz, 1 H, H-6b), 2.04 (s, 3 H, H-18), 1.63-1.67 (m, 1 H, H-19b), 1.33 (m, 1 H, H-7), 1.22 (s, 3 H, H-16), 1.10 (s, 3 H, H-17).
Remove benzoyl-2-(-trifluoromethoxy benzoyl)-7-deoxidation-7 β, and 8 β-methylene radical-baccatin III (V-5d): 1H NMR (400 MHz, CDCl 3) δ 8.07 (d, J=7.4 Hz, 1 H, Ph-H), 8.02 (s, 1 H, Ph-H), 7.54 (t, J=7.8 Hz, 1 H, Ph-H), 7.47 (d, J=7.8 Hz, 1 H, Ph-H), 6.34 (s, 1 H, H-10), 5.60 (d, J=7.4 Hz, 1 H, H-2), 4.83 (t, J=8.2 Hz, 1 H, H-13), 4.76 (d, J=4.3 Hz, 1 H, H-5), 4.27 (d, J=8.2 Hz, 1 H, H-20a), 4.19 (d, J=7.4 Hz, 1 H, H-3), 4.02 (d, J=8.2 Hz, 1 H, H-20b), 2.48 (dt, J=16.0,4.3 Hz, 1 H, H-6a), 2.23-2.36 (m, 3 H, H-14 and H-19a), 2.24 (s, 3 H, C H 3CO in C-10), 2.21 (s, 3 H, C H 3CO in C-4), 2.10 (d, J=16.0 Hz, 1 H, H-6b), 2.02 (s, 3 H, H-18), 1.64 (m, 1 H, H-19b), 1.34 (m, 1 H, H-7), 1.21 (s, 3 H, H-16), 1.09 (s, 3 H, H-17).
Remove benzoyl-2-(-fluoro benzoyl)-7-deoxidation-7 β, and 8 β-methylene radical-baccatin III (V-5e): 1H NMR (400 MHz, CDCl 3) δ 8.47 (s, 1 H, Ph-H), 8.31 (d, J=7.8 Hz, 1 H, Ph-H), 7.88 (d, J=7.4 Hz, 1 H, Ph-H), 7.65 (t, J=7.8 Hz, 1 H, Ph-H), 6.35 (s, 1 H, H-10), 5.61 (d, J=7.8 Hz, 1 H, H-2), 4.83 (t, J=7.4 Hz, 1 H, H-13), 4.77 (d, J=3.5 Hz, 1 H, H-5), 4.25 (d, J=8.2 Hz, 1 H, H-20a), 4.20 (d, J=7.4 Hz, 1 H, H-3), 4.02 (d, J=8.2 Hz, 1 H, H-20b), 2.48 (dt, J=16.4,4.3 Hz, 1 H, H-6a), 2.23-2.35 (m, 3 H, H-14 and H-19a), 2.25 (s, 3 H, C H 3CO in C-10), 2.21 (s, 3 H, C H 3CO in C-4), 2.10 (d, J=16.0 Hz, 1 H, H-6b), 2.03 (s, 3 H, H-18), 1.63-1.67 (m, 1 H, H-19b), 1.35 (m, 1 H, H-7), 1.22 (s, 3 H, H-16), 1.10 (s, 3 H, H-17).
Remove benzoyl-2-(-chloroformyl)-7-deoxidation-7 β, and 8 β-methylene radical-baccatin III (V-5f): 1H NMR (400 MHz, CDCl 3) δ 8.15 (s, 1 H, Ph-H), 8.00 (d, J=7.8 Hz, 1 H, Ph-H), 7.59 (d, J=7.8 Hz, 1 H, Ph-H), 7.43 (t, J=7.8 Hz, 1 H, Ph-H), 6.34 (s, 1 H, H-10), 5.57 (d, J=7.8 Hz, 1 H, H-2), 4.82 (t, J=7.4 Hz, 1 H, H-13), 4.76 (d, J=3.5 Hz, 1 H, H-5), 4.28 (d, J=8.2 Hz, 1 H, H-20a), 4.18 (d, J=7.8 Hz, 1 H, H-3), 4.01 (d, J=8.6 Hz, 1 H, H-20b), 2.48 (dt, J=16.0,4.3 Hz, 1 H, H-6a), 2.22-2.34 (m, 3 H, H-14 and H-19a), 2.27 (s, 3 H, C H 3CO in C-10), 2.21 (s, 3 H, C H 3CO in C-4), 2.09 (d, J=16.0 Hz, 1 H, H-6b), 2.02 (s, 3 H, H-18), 1.62-1.65 (m, 1 H, H-19b), 1.35 (m, 1 H, H-7), 1.21 (s, 3 H, H-16), 1.09 (s, 3 H, H-17).
Remove benzoyl-2-(-cyano group benzoyl)-7-deoxidation-7 β, and 8 β-methylene radical-baccatin III (V-5g): 1H NMR (400 MHz, CDCl 3) δ 8.45 (s, 1 H, Ph-H), 8.34 (d, J=7.8 Hz, 1 H, Ph-H), 7.90 (d, J=7.4 Hz, 1 H, Ph-H), 7.65 (t, J=7.8 Hz, 1 H, Ph-H), 6.34 (s, 1 H, H-10), 5.59 (d, J=7.4 Hz, 1 H, H-2), 4.83 (t, J=7.4 Hz, 1 H, H-13), 4.76 (broad s, 1 H, H-5), 4.19-4.23 (m, 2 H, H-20a and H-3), 4.01 (d, J=8.6 Hz, 1 H, H-20b), 2.48 (dt, J=16.4,4.3 Hz, 1 H, H-6a), 2.22-2.35 (m, 3 H, H-14 and H-19a), 2.28 (s, 3 H, C H 3CO in C-10), 2.21 (s, 3 H, C H 3CO in C-4), 2.10 (d, J=16.4 Hz, 1 H, H-6b), 2.03 (s, 3 H, H-18), 1.64 (m, 1 H, H-19b), 1.35 (m, 1 H, H-7), 1.21 (s, 3 H, H-16), 1.10 (s, 3 H, H-17).
Remove benzoyl-2-(-triazobenzene formyl radical)-7-deoxidation-7 β, and 8 β-methylene radical-baccatin III (V-5h): 1H NMR (400 MHz, CDCl 3) δ 7.90 (d, J=7.4 Hz, 1 H, Ph-H), 7.81 (s, 1 H, Ph-H), 7.48 (t, J=7.8 Hz, 1 H, Ph-H), 7.25 (s, 1 H, Ph-H), 6.34 (s, 1 H, H-10), 5.62 (d, J=7.8 Hz, 1 H, H-2), 4.83 (t, J=7.1 Hz, 1 H, H-13), 4.75 (d, J=3.9 Hz, 1 H, H-5), 4.30 (d, J=8.6 Hz, 1 H, H-20a), 4.18 (d, J=7.4 Hz, 1 H, H-3), 4.02 (d, J=8.6 Hz, 1 H, H-20b), 2.48 (dt, J=16.0,4.3 Hz, 1 H, H-6a), 2.23-2.35 (m, 3 H, H-14 and H-19a), 2.26 (s, 3 H, C H 3CO in C-10), 2.20 (s, 3 H, C H 3CO in C-4), 2.09 (d, J=16.0 Hz, 1 H, H-6b), 2.02 (s, 3 H, H-18), 1.62-1.65 (m, 1 H, H-19b), 1.34 (m, 1 H, H-7), 1.21 (s, 3 H, H-16), 1.10 (s, 3 H, H-17).
Remove benzoyl-2-(m-trifluoromethyl benzoyl)-7-deoxidation-7 β, 8 β-methylene radical-10-acetoxyl group-Docetaxel (I-1a):
Figure 450421DEST_PATH_IMAGE016
Intermediate 2-is removed benzoyl-2-(m-trifluoromethyl benzoyl)-7-deoxidation-7 β, 8 β-methylene radical-baccatin III ( V-5a) (68.0 mg; 0.11 mmol); (3R; 4S)-1-t-BOC-3-OTES-beta-lactam (48.5 mg; 0.13 mmol) be dissolved among the exsiccant THF (15 mL); under the argon shield reaction solution is cooled to-40 ° of C; drip alkali LiHMDS (165.0 μ L; 0.17 mmol; 1.0 M in THF); continue reaction 1.5 h; after detection reaction finishes, add saturated ammonium chloride (10 mL) termination reaction, mixture is extracted with ethyl acetate (30 mL * 3); merge organic phase; use 1 M hydrochloric acid (10 mL * 3) successively; saturated sodium bicarbonate aqueous solution (10 mL * 3); saturated sodium-chloride water solution (10 mL * 3) washing, anhydrous sodium sulfate drying concentrates and obtains the spumescence solid.Crude product is dissolved in THF (15 mL); add TBAF (86.4 mg; 0.33 mmol); 40 ° of C react 3 h down; add saturated ammonium chloride (10 mL) termination reaction; mixture is extracted with ethyl acetate (30 mL * 3); merge organic phase; use 1 M hydrochloric acid (10 mL * 3) successively; saturated sodium bicarbonate aqueous solution (10 mL * 3); saturated sodium-chloride water solution (10 mL * 3) washing; anhydrous sodium sulfate drying; concentrate and obtain the spumescence solid; crude product obtains white powder solid 2-through column chromatography for separation (petrol ether/ethyl acetate=3/1) and removes benzoyl-2-(m-trifluoromethyl benzoyl)-7-deoxidation-7 β, 8 β-methylene radical-10-acetoxyl group-Docetaxel ( I-1a)(88.2 mg, 86% yield for two steps): 1H NMR (400 MHz, CDCl 3) δ 8.47 (s, 1 H, Ph-H), 8.34 (d, J=7.8 Hz, 1 H, Ph-H), 7.89 (d, J=7.3 Hz, 1 H, Ph-H), 7.67 (t, J=7.8 Hz, 1 H, Ph-H), 7.31-7.39 (m, 5 H, Ph-H), 6.33 (s, 1 H, H-10), 6.20 (brt, 1 H, H-13), 5.64 (d, J=7.8 Hz, 1 H, H-2), 5.31 (d, J=8.8 Hz, 1 H, CON H), 5.24 (brd, J=7.8 Hz, 1 H, H-3 '), 4.75 (broad s, 1 H, H-5), 4.59 (s, 1 H, H-2 '), 4.27 (d, J=8.3 Hz, 1 H, H-20a), 4.12 (d, J=7.8 Hz, 1 H, H-3), 4.02 (d, J=8.3 Hz, 1 H, H-20b), 2.46 (dt like, J=16.6,1 H, H-6a), 2.33 (s, 3 H, C H 3CO in C-4), 2.24-2.29 (m, 3 H, H-19a and H-14), 2.21 (s, 3 H, C H 3CO in C-10), 2.11 (d, J=15.6 Hz, 1 H, H-6b), 1.85 (s, 3 H, C H 3In C-18), 1.67 (t like, 1 H, H-19b), 1.36 (m, 1 H, H-7), 1.25-1.28 (m, 15 H, Me 3C, H-16 and H-17).
According to identical method can prepare other the substituted butt joint product of C-2 benzoyl ( I-1b ~ I-1h):
2-removes benzoyl-2-(-methyl benzoyl)-7-deoxidation-7 β, 8 β-methylene radical-10-acetoxyl group-Docetaxel (I-1b): 1H NMR (400 MHz, CDCl 3) δ 7.98 (s, 1 H, Ph-H), 7.94 (d, J=5.9 Hz, 1 H, Ph-H), 7.28-7.39 (m, 7 H, Ph-H), 6.32 (s, 1 H, H-10), 6.26 (brt, 1 H, H-13), 5.64 (d, J=7.0 Hz, 1 H, H-2), 5.36 (broad d, 1 H, CON H), 5.26 (broad d, J=7.8 Hz, 1 H, H-3 '), 4.73 (broad s, 1 H, H-5), 4.61 (s, 1 H, H-2 '), 4.31 (d, J=8.6 Hz, 1 H, H-20a), 4.08 (d, J=7.0 Hz, 1 H, H-3), 4.02 (d, J=8.6 Hz, 1 H, H-20b), 3.33 (broad s, 1 H), 2.43-2.47 (m, 1 H, H-6a), 2.43 (s, 1 H, PhC H 3), 2.37 (s, 3 H, C H 3CO in C-4), 2.24-2.26 (m, 3 H, H-19a and H-14), 2.20 (s, 3 H, C H 3CO in C-10), 2.09 (d, J=16.0 Hz, 1 H, H-6b), 1.84 (s, 3 H, C H 3In C-18), 1.66 (t like, 1 H, H-19b), 1.36 (m, 1 H, H-7), 1.25-1.28 (m, 15 H, Me 3C, H-16 and H-17).
Remove benzoyl-2-(-anisoyl)-7-deoxidation-7 β, 8 β-methylene radical-10-acetoxyl group-Docetaxel (I-1c): 1H NMR (400 MHz, CDCl 3) δ 7.75 (d, J=7.8 Hz, 2 H, Ph-H), 7.74 (s, 1 H, Ph-H), 7.31-7.43 (m, 6 H, Ph-H), 7.14 (d, J=7.4 Hz, 1 H, Ph-H), 6.32 (s, 1 H, H-10), 6.26 (brt, 1 H, H-13), 5.66 (d, J=7.4 Hz, 1 H, H-2), 5.35 (d, J=9.0 Hz, 1 H, CON H), 5.28 (brd, J=7.8 Hz, 1 H, H-3 '), 4.73 (broad s, 1 H, H-5), 4.60 (s, 1 H, H-2 '), 4.36 (d, J=8.6 Hz, 1 H, H-20a), 4.08 (d, J=7.8 Hz, 1 H, H-3), 4.03 (d, J=8.6 Hz, 1 H, H-20b), 2.46 (dt, J=15.3,4.8 Hz, 1 H, H-6a), 2.36 (s, 3 H, C H 3CO in C-4), 2.20 (s, 3 H, C H 3CO in C-10), 2.22-2.24 (m, 3 H, H-19a and H-14), 2.10 (d, J=16.0 Hz, 1 H, H-6b), 1.84 (s, 3 H, C H 3In C-18), 1.67 (m, 1 H, H-19b), 1.33 (m, 1 H, H-7), 1.26 (m, 15 H, Me 3C, H-16 and H-17).
Remove benzoyl-2-(-trifluoromethoxy benzoyl)-7-deoxidation-7 β, 8 β-methylene radical-10-acetoxyl group-Docetaxel (I-1d): 1H NMR (400 MHz, CDCl 3) δ 8.47 (s, 1 H, Ph-H), 8.34 (d, J=7.8 Hz, 1 H, Ph-H), 7.89 (d, J=7.3 Hz, 1 H, Ph-H), 7.67 (t, J=7.8 Hz, 1 H, Ph-H), 7.31-7.39 (m, 5 H, Ph-H), 6.33 (s, 1 H, H-10), 6.20 (brt, 1 H, H-13), 5.64 (d, J=7.8 Hz, 1 H, H-2), 5.31 (d, J=8.8 Hz, 1 H, CON H), 5.24 (brd, J=7.8 Hz, 1 H, H-3 '), 4.75 (broad s, 1 H, H-5), 4.59 (s, 1 H, H-2 '), 4.27 (d, J=8.3 Hz, 1 H, H-20a), 4.12 (d, J=7.8 Hz, 1 H, H-3), 4.02 (d, J=8.3 Hz, 1 H, H-20b), 2.46 (dt like, J=16.6,1 H, H-6a), 2.33 (s, 3 H, C H 3CO in C-4), 2.24-2.29 (m, 3 H, H-19a and H-14), 2.21 (s, 3 H, C H 3CO in C-10), 2.11 (d, J=15.6 Hz, 1 H, H-6b), 1.85 (s, 3 H, C H 3In C-18), 1.67 (t like, 1 H, H-19b), 1.36 (m, 1 H, H-7), 1.25-1.28 (m, 15 H, Me 3C, H-16 and H-17).
Remove benzoyl-2-(-fluoro benzoyl)-7-deoxidation-7 β, 8 β-methylene radical-10-acetoxyl group-Docetaxel (I-1e): 1H NMR (400 MHz, CDCl 3) δ 7.95 (d, J=7.7 Hz, 1 H, Ph-H), 7.84 (d, J=9.0 Hz, 1 H, Ph-H), 7.32-7.54 (m, 7 H, Ph-H), 6.32 (s, 1 H, H-10), 6.25 (brt, 1 H, H-13), 5.63 (d, J=7.8 Hz, 1 H, H-2), 5.33 (d, J=8.8 Hz, 1 H, CON H), 5.24 (brd, J=7.8 Hz, 1 H, H-3 '), 4.75 (broad s, 1 H, H-5), 4.59 (s, 1 H, H-2 '), 4.27 (d, J=8.3 Hz, 1 H, H-20a), 4.12 (d, J=7.8 Hz, 1 H, H-3), 4.02 (d, J=8.3 Hz, 1 H, H-20b), 2.46 (dt like, J=16.6,1 H, H-6a), 2.33 (s, 3 H, C H 3CO in C-4), 2.24-2.29 (m, 3 H, H-19a and H-14), 2.21 (s, 3 H, C H 3CO in C-10), 2.11 (d, J=15.6 Hz, 1 H, H-6b), 1.85 (s, 3 H, C H 3In C-18), 1.67 (t like, 1 H, H-19b), 1.36 (m, 1 H, H-7), 1.25-1.28 (m, 15 H, Me 3C, H-16 and H-17);
2-removes benzoyl-2-(-chlorobenzene formacyl)-7-deoxidation-7 β, 8 β-methylene radical-10-acetoxyl group-Docetaxel (I-1f): 1H NMR (400 MHz, CDCl 3) δ 8.16 (s, 1 H, Ph-H), 8.04 (d, J=7.8 Hz, 1 H, Ph-H), 7.72 (dd, J=5.9,3.5 Hz, 1 H, Ph-H), 7.56 (d, J=8.2 Hz, 1 H, Ph-H), 7.53 (dd, J=5.9,3.5 Hz, 1 H, Ph-H), 7.46 (t, J=7.8 Hz, 1 H, Ph-H), 7.30-7.41 (m, 3 H, Ph-H), 6.35 (s, 1 H, H-10), 6.22 (brt, 1 H, H-13), 5.62 (d, J=7.4 Hz, 1 H, H-2), 5.33 (d like, 1 H, CON H), 5.27 (brd, 1 H, H-3 '), 4.74 (broad s, 1 H, H-5), 4.59 (s, 1 H, H-2 '), 4.30 (d, J=8.6 Hz, 1 H, H-20a), 4.09 (d, J=7.8 Hz, 1 H, H-3), 4.01 (d, J=8.6 Hz, 1 H, H-20b), 2.45 (dt, J=16.1,4.3 Hz, 1 H, H-6a), 2.36 (s, 3 H, C H 3CO in C-4), 2.22-2.26 (m, 3 H, H-19a and H-14), 2.21 (s, 3 H, C H 3CO in C-10), 2.14 (d, J=13.7 Hz, 1 H, H-6b), 1.84 (s, 3 H, C H 3In C-18), 1.67 (t like, 1 H, H-19b), 1.35 (m, 1 H, H-7), 1.25-1.28 (m, 15 H, Me 3C, H-16 and H-17);
2-removes benzoyl-2-(-cyano group benzoyl)-7-deoxidation-7 β, 8 β-methylene radical-10-acetoxyl group-Docetaxel (I-1g): 1H NMR (400 MHz, CDCl 3) δ 8.48 (s, 1 H, Ph-H), 8.38 (d, J=7.7 Hz, 1 H, Ph-H), 7.88 (d, J=7.7 Hz, 1 H, Ph-H), 7.67 (td, J=7.7,2.6 Hz, 1 H, Ph-H), 7.31-7.39 (m, 5 H, Ph-H), 6.33 (d, J=2.6 Hz, 1 H, H-10), 6.25 (brt, 1 H, H-13), 5.63 (d, J=6.2 Hz, 1 H, H-2), 5.33 (dd like, J=7.7 Hz, 2 H, CON H), 4.74 (broad s, 1 H, H-5), 4.62 (s, 1 H, H-2 '), 4.23 (d, J=7.7 Hz, 1 H, H-20a), 4.12 (d, J=6.2 Hz, 1 H, H-3), 4.01 (d, J=7.7 Hz, 1 H, H-20b), 2.46 (dt like, J=15.7,1 H, H-6a), 2.37 (s, 3 H, C H 3CO in C-4), 2.24-2.33 (m, 3 H, H-19a and H-14), 2.21 (s, 3 H, C H 3CO in C-10), 2.11 (d, J=16.1 Hz, 1 H, H-6b), 1.85 (s, 3 H, C H 3In C-18), 1.66 (t like, 1 H, H-19b), 1.36 (m, 1 H, H-7), 1.25-1.28 (m, 15 H, Me 3C, H-16 and H-17).
Remove benzoyl-2-(-triazobenzene formyl radical)-7-deoxidation-7 β, 8 β-methylene radical-10-acetoxyl group-Docetaxel (I-1h): 1H NMR (400 MHz, CDCl 3) δ 7.93 (d, J=7.8 Hz, 1 H, Ph-H), 7.86 (s, 1 H, Ph-H), 7.48 (t, J=7.8 Hz, 1 H, Ph-H), and 7.22-7.41 (m, 6 H, Ph-H), 6.33 (s, 1 H, H-10), 6.26 (brt, 1 H, H-13), 5.66 (d, J=7.8 Hz, 1 H, H-2), 5.34 (d like, 1 H, CON H), 5.32 (broad d, 1 H, H-3 '), 4.74 (d, 1 H, J=3.4 Hz, H-5), 4.60 (s, 1 H, H-2 '), 4.33 (d, J=8.8 Hz, 1 H, H-20a), 4.10 (d, J=7.3 Hz, 1 H, H-3), 4.03 (d, J=8.8 Hz, 1 H, H-20b), 3.25 (broad s, 1H), 2.46 (dt like, J=16.1,1 H, H-6a), 2.39 (s, 3 H, C H 3CO-in C-4), 2.23-2.26 (m, 3 H, H-19a and H-14), 2.21 (s, 3 H, C H 3CO-in C-10), 2.11 (d, J=16.1 Hz, 1 H, H-6b), 1.85 (s, 3 H ,-C H 3In C-18), 1.65 (t like, 1 H, H-19b), 1.38 (m, 1 H, H-7), 1.25-1.26 (m, 15 H, Me 3C-, H-16 and H-17).
The side chain general formula ( VI) shown in compound and female ring general formula ( V) shown in compound butt joint product the preparation method with ( I-1a ~ I-1h) similar:
3'-(2,2-difluoroethylene base)-7-deoxidation-7 β, 8 β-methylene radical-10-acetoxyl group-Docetaxel (I-2a). 1H NMR (400 MHz, CDCl 3) δ 8.17 (d, J=7.4 Hz, 2 H, Ph-H), 7.61 (t, J=7.4 Hz, 1 H, Ph-H), 7.51 (t, J=7.8 Hz, 2 H, Ph-H), 6.33 (s, 1 H, H-10), 6.27 (broad t, 1 H, H-13), 5.66 (d, J=7.8 Hz, 1 H, H-2), 4.90 (d, J=2.7 Hz, 1 H), 4.74 (d, J=3.5 Hz, 1 H, H-5), 4.62-4.56 (m, 1 H, H-2 '), 4.32 (d, J=8.6 Hz, 1 H, H-20a), (4.28 broad s, 1 H), 4.09 (d, J=7.8 Hz, 1 H, H-3), 4.04 (d, J=8.2 Hz, 1 H), 3.44 (broad s, 1 H ,-O H), 2.50-2.42 (m, 2 H, H-6a and H-14a), 2.39 (s, 3 H, C H 3CO-in C-4), 2.27-2.21 (m, 2 H, H-19a and H-14b), 2.21 (s, 3 H, C H 3CO-in C-10), 2.11 (d, J=16.0 Hz, 1 H, H-6b), 1.86 (s, 3 H ,-C H 3In C-18), 1.67 (t like, 1 H, H-19b), 1.37 (m, 1 H, H-7), 1.25 (m, 15 H, Me 3C-, H-16 and H-17).
Methyl isophthalic acid-propenyl)-7-deoxidation-7 β, 8 β-methylene radical-10-acetoxyl group-Docetaxel (I-2b). 1H NMR (400 MHz, CDCl 3) δ 8.15 (d, J=7.3 Hz, 2 H, Ph-H), 7.59 (t, J=7.3 Hz, 1 H, Ph-H), 7.47 (t, J=7.7 Hz, 2 H, Ph-H), 6.33 (s, 1 H, H-10), 6.19 (broad t, J=8.8 Hz, 1 H, H-13), 5.65 (d, J=7.7 Hz, 1 H), 4.73 (d, J=3.7 Hz, 1 H), 4.59 (d, J=9.9 Hz, 1 H), (4.29 d, J=8.4 Hz, 1 H), 4.16 (d, J=4.4 Hz, 2 H), 4.08 (t like, J=8.8,7.7 Hz, 2 H), 3.26 (d, J=5.1 Hz, 1 H), 2.44-2.49 (m, 2 H), 2.35 (s, 3 H, C H 3CO-in C-4), 2.32-2.38 (m, 1 H), 2.21-2.25 (m, 2 H), 2.20 (s, 3 H, C H 3CO-in C-10), 2.09 (d, J=16.1 Hz, 1 H, H-6b), 1.86 (s, 3 H, C H 3In C-18), 1.68 (m, 6 H), 1.33-1.38 (m, 1 H, H-7), 1.24-1.28 (m, 15 H, Me 3C-, H-16 and H-17), 0.99 (s, 3 H), 0.98 (s, 3 H).
Methyl-propyl)-7-deoxidation-7 β, 8 β-methylene radical-10-acetoxyl group-Docetaxel (I-2c). 1H NMR (400 MHz, CDCl 3) δ 8.14 (d, J=7.5 Hz, 2 H, Ph-H), 7.60 (t, J=7.5 Hz, 1 H, Ph-H), 7.49 (t, J=7.5 Hz, 2 H, Ph-H), 6.33 (s, 1 H, H-10), 6.16 (broad t, 1 H, H-13), (5.66 d, J=7.5 Hz, 1 H), 5.32 (d, J=7.5 Hz, 1 H), 4.73-4.79 (m, 2 H), (4.30 d, J=8.7 Hz, 1 H), 4.19 (broad s, 1 H), 4.02-4.14 (m, 2 H), 3.38 (broad s, 1 H), 2.36-2.48 (m, 3 H), 2.34 (s, 3 H), 2.21-2.24 (m, 1 H), 2.20 (s, 3 H), 2.09 (d, J=17.4 Hz, 1 H), (1.87 s, 3 H), 1.77 (s, 6 H), (1.66 m, 1 H), 1.32 (m, 9 H), (1.26 s, 3 H), 1.23 (s, 3 H).
Remove tertbutyloxycarbonyl- 3'-(2-methylpropenyl)-7-deoxidation-7 β, 8 β-methylene radical-10-acetoxyl group-Docetaxel (II-a):
With the 3'-(2-methylpropenyl) that has prepared -7-deoxidation-7 β, 8 β-methylene radical-10-acetoxyl group-Docetaxel ( I-2b) (1.8 g, 2.22 mmol) be dissolved in CH 2Cl 2(30 mL), 0 ° of C adds the dichloromethane solution (10 mL, 25% total volume) of trifluoroacetic acid down, continues reaction 1.5 h, after the TLC detection reaction raw material residue, uses the saturated sodium bicarbonate termination reaction, water CH 2Cl 2(100 mL * 3) extraction, merge organic phase, use saturated sodium bicarbonate aqueous solution (100 mL * 3), saturated sodium-chloride water solution (100 mL * 3) washing successively, anhydrous sodium sulfate drying, concentrate, crude product obtains white fish scale shape solid 3'-N-through column chromatography for separation (petrol ether/ethyl acetate=1/3) and removes tertbutyloxycarbonyl-3'-(2-methylpropenyl)-7-deoxidation-7 β, 8 β-methylene radical-10-acetoxyl group-Docetaxel ( II-a) (1.48 g, 94% yield): 1H NMR (400 MHz, CDCl 3) δ 8.11 (d, J=7.3 Hz, 2 H, Ph-H), 7.62 (t, J=7.3 Hz, 1 H, Ph-H), 7.48 (t, J=7.8 Hz, 2 H, Ph-H), 6.34 (s, 1 H, H-10), 6.19 (broad t, 1 H, H-13), 5.67 (d, J=7.8 Hz, 1 H), 5.25 (d, J=8.8 Hz, 1 H), 4.74 (d, J=8.8 Hz, 1 H), (4.32 d, J=8.8 Hz, 1 H), 4.05-3.89 (m, 3 H), 2.47 (dt, J=16.1,4.4 Hz, 1 H), 2.34 (s, 3 H), 2.24-2.26 (m, 2 H), 2.21 (s, 3 H), 2.11 (d, J=16.1 Hz, 1 H), 1.89 (s, 3 H), (1.73 s, 3 H), 1.71 (s, 3 H), (1.66 t like, 1 H), 1.38 (m, 1 H), (1.28 s, 3 H), 1.25 (s, 3 H).
According to identical method can prepare the intermediate that C-3' amino takes off the Boc protecting group ( II-b):
3'-N-removes tertbutyloxycarbonyl- 3'-(2-methyl-propyl)-7-deoxidation-7 β, 8 β-methylene radical-10-acetoxyl group-Docetaxel (II-b): 1H NMR (400 MHz, CDCl 3) δ 8.16 (d, J=7.8 Hz, 2 H, Ph-H), 7.68 (t, J=7.3 Hz, 1 H, Ph-H), 7.54 (t, J=7.3 Hz, 2 H, Ph-H), 6.39 (s, 1 H, H-10), 6.28 (broad t, J=8.8 Hz, 1 H, H-13), 5.72 (d, J=7.3 Hz, 1 H, H-2), 4.79 (d like, 1 H), 4.37 (d, J=8.8 Hz, 1 H), (4.16 d, J=7.3 Hz, 1 H), 4.09 (d, J=7.8 Hz, 2 H), 4.08 (t like, J=8.8,7.7 Hz, 2 H), 3.30 (broad s, 1 H), 2.56 (dt like, J=7.8 Hz, 1 H, H-6a), 2.39 (s, 3 H, C H 3CO in C-4), 2.29-2.41 (m, 5 H), 2.26 (s, 3 H, C H 3CO in C-10), 2.16 (d, J=16.1 Hz, 1 H, H-6b), 1.96 (s, 3 H, C H 3In C-18), 1.71 (t like, 1 H), 1.38-1.43 (m, 1 H, H-7), 1.32 (s, 3 H), 1.30 (s, 3 H), 1.05 (d, J=7.3 Hz, 3 H), 1.01 (d, J=7.3 Hz, 3 H).
Remove tertbutyloxycarbonyl- 3'-N-((E)-2-methyl-2-butene acyl group)-(2-methyl isophthalic acid-propenyl)-7-deoxidation-7 β, 8 β-methylene radical-10-acetoxyl group-Docetaxel (I-3a):
Figure 243933DEST_PATH_IMAGE018
The 3'-N-for preparing is removed tertbutyloxycarbonyl-3'-(2-methylpropenyl)-7-deoxidation-7 β, 8 β-methylene radical-10-acetoxyl group-Docetaxel ( II-a) (78.0 mg, 0.11 mmol), triethylamine (30.7 μ L, 0.22 mmol) be dissolved in CH 2Cl 2(10 mL) adds condensing agent (EDCHCl) (31.8 mg, 0.17 mmol) and trans-2,3-dimethylacrylic acid (14.3 mg, 0.17 mmol), stirring at room 4 h, after the TLC detection reaction raw material residue, use the saturated ammonium chloride termination reaction, water CH 2Cl 2(30 mL * 3) extraction; merge organic phase; use saturated sodium bicarbonate aqueous solution (20 mL * 3), saturated sodium-chloride water solution (20 mL * 3) washing successively; anhydrous sodium sulfate drying; concentrate; crude product obtains the solid 3'-N-of white foam shape through column chromatography for separation (petrol ether/ethyl acetate=3/1) and removes tertbutyloxycarbonyl-3'-N-((E)-2-methyl-2-butene acyl group)-(2-methyl isophthalic acid-propenyl)-7-deoxidation-7 β, 8 β-methylene radical-10-acetoxyl group-Docetaxel ( I-3a) (74.9 mg, 86% yield): 1H NMR (400 MHz, CDCl 3) δ 8.14 (d, J=7.8 Hz, 2 H, Ph-H), 7.47 (t, J=7.0 Hz, 1 H, Ph-H), 7.47 (t, J=7.8 Hz, 2 H, Ph-H), 6.36 (dd, J=14.1,7.0 Hz, 1 H), 6.32 (s, 1 H, H-10), 6.15 (broad t, J=8.6 Hz, 1 H, H-13), 5.99 (d, J=8.2 Hz, 1 H), 5.39 (d, J=9.0 Hz, 1 H ,-CON H-), 5.09 (td, J=8.2,3.1 Hz, 1 H), 4.73 (d, J=3.5 Hz, 1 H, H-5), 4.30 (d, J=8.6 Hz, 1 H, H-20a), (4.27 s, 1 H), 4.09-4.07 (m, 2 H, H-20b and H-3), 3.76 (broad s, 1H), 2.49-2.33 (m, 3 H), 2.35 (s, 3 H, C H 3CO-), 2.26-2.22 (m, 1 H), 2.20 (s, 3 H, C H 3CO-), 2.09 (d, J=15.7 Hz, 1 H, H-6b), 1.85 (s, 3 H-C H 3In C-18), 1.81-1.68 (m, 13 H), 1.39-1.31 (m, 1 H, H-7), 1.29-1.21 (m, 6 H ,-C H 3 In C-16 and C-17).
According to identical method can prepare the compound that other C-3' amino N replaces ( I-3b ~ I-3c):
3'-N-removes tertbutyloxycarbonyl- 3'-N-((E)-2-butylene acyl group)-(2-methyl isophthalic acid-propenyl)-7-deoxidation-7 β, 8 β-methylene radical-10-acetoxyl group-Docetaxel (I-3c): 1H NMR (400 MHz, CDCl 3) δ 8.14 (d, J=7.0 Hz, 2 H, Ph-H), 7.60 (t, J=7.4 Hz, 1 H, Ph-H), 7.47 (t, J=7.8 Hz, 2 H, Ph-H), 6.75-6.69 (m, 1H), 6.32 (s, 1 H, H-10), 6.15 (broad t, 1 H, H-13), 5.76 (d, J=8.6 Hz, 1 H), 5.71 (s, 1H), 5.67 (d, J=7.8 Hz, 1 H), 5.39 (d, J=9.0 Hz, 1 H ,-CON H-), 5.09 (td, J=8.6,2.7 Hz, 1 H), 4.73 (d, J=3.5 Hz, 1 H, H-5), 4.30 (d, J=8.6 Hz, 1 H, H-20a), 4.26 (d, J=2.3 Hz, 1 H), (4.08 d, J=8.2 Hz, 2 H, H-20b and H-3), (2.49-2.37 m, 3 H), 2.34 (s, 3 H C H 3CO-), 2.25-2.21 (m, 1 H), 2.20 (s, 3 H C H 3CO-), 2.09 (d, J=14.9 Hz, 1 H, H-6b), 1.85 (s, 3 H ,-C H 3 In C-18), 1.77 (s, 9 H), 1.68-1.65 (m, 1 H, H-19b), 1.36 (m, 1 H, H-7), 1.26-1.23 (m, 6 H ,-C H 3 In C-16 and C-17).
Remove tertbutyloxycarbonyl- 3'-N-((E)-2-methyl-2-butene acyl group)-(2-methyl-propyl)-7-deoxidation-7 β, 8 β-methylene radical-10-acetoxyl group-Docetaxel (I-3d): 1H NMR (400 MHz, CDCl 3) δ 8.16 (d, J=7.8 Hz, 2 H, Ph-H), 7.59 (t, J=7.4 Hz, 1 H, Ph-H), 7.47 (t, J=7.8 Hz, 2 H, Ph-H), 6.32 (s, 1 H, H-10), 6.29 (dd, J=13.7,7.0 Hz, 1 H), 6.16 (broad t, 1 H, H-13), 5.79 (d, J=9.4 Hz, 1 H), 5.67 (d, J=7.8 Hz, 1 H, H-2), 4.73 (d, J=3.1 Hz, 1 H, H-5), 4.49 (m, 1 H), 4.29 (d, J=8.6 Hz, 1 H, H-20a), 4.23 (broad s, 1 H, H-2'), 4.11-4.07 (m, 2 H, H-20b and H-3), 3.59 (broad s, 1 H ,-O H), 2.50-2.33 (m, 3 H), 2.39 (s, 3 H, C H 3CO-), 2.28-2.20 (m, 1 H), 2.20 (s, 3 H, C H 3CO-), 2.10 (d, J=15.7 Hz, 1 H, H-6b), 1.85 (s, 3 H ,-C H 3In C-18), 1.85-1.67 (m, 8 H), 1.43-1.37 (m, 3 H), 1.27-1.23 (m, 6 H ,-C H 3 In C-16 and C-17), 1.00 (s, 3 H), 0.98 (s, 3 H).
Remove tertbutyloxycarbonyl- 3'-N-((E)-2-butylene acyl group)-(2-methyl-propyl)-7-deoxidation-7 β, 8 β-methylene radical-10-acetoxyl group-Docetaxel (I-3e): 1H NMR (400 MHz, CDCl 3) δ 8.16 (d, J=7.0 Hz, 2 H, Ph-H), 7.59 (t, J=7.4 Hz, 1 H, Ph-H), 7.47 (t, J=7.8 Hz, 2 H, Ph-H), 6.68-6.63 (m, 1 H, CH 3C H=CH-), 6.32 (s, 1 H, H-10), 6.16 (broad t, J=8.6 Hz, 1 H, H-13), 5.72 (dd, J=15.3,1.6 Hz, 1 H), 5.67 (d, J=7.4 Hz, 1 H, H-2), 5.58 (d, J=9.0 Hz, 1 H ,-CON H-), 4.73 (d, J=3.6 Hz, 1 H, H-5), (4.48 m, 1 H), 4.29 (d, J=8.6 Hz, 1 H, H-20a), 4.22 (broad s, 1 H, H-2'), 4.11 (d, J=8.6 Hz, 1 H, H-20b), 4.07 (d, J=7.8 Hz, 1 H, H-3), 3.61 (broad s, 1 H ,-O H), 2.50-2.44 (m, 3 H), 2.37 (s, 3 H, C H 3CO-), 2.26-2.20 (m, 1 H), 2.20 (s, 3 H, C H 3CO-), 2.10 (d, J=15.7 Hz, 1 H, H-6b), 1.84 (s, 3 H ,-C H 3In C-18), 1.84-1.59 (m, 5 H), 1.40-1.35 (m, 3 H), 1.27-1.23 (m, 6 H ,-C H 3 In C-16 and C-17), 1.00-0.98 (m, 6 H).
Remove tertbutyloxycarbonyl- 3'-N-(3,3'-dimethyl propylene enoyl-)-(2-methyl-propyl)-7-deoxidation-7 β, 8 β-methylene radical-10-acetoxyl group-Docetaxel (I-3f): 1H NMR (400 MHz, CDCl 3) δ 8.15 (d, J=7.4 Hz, 2 H, Ph-H), 7.58 (t, J=7.4 Hz, 1 H, Ph-H), 7.46 (t, J=7.8 Hz, 2 H, Ph-H), 6.32 (s, 1 H, H-10), 6.16 (broad t, 1 H, H-13), 5.66 (d, J=7.4 Hz, 1 H, H-2), 5.50 (s, 1 H), 5.45 (d, J=9.4 Hz, 1 H ,-CON H-), 4.73 (d, J=3.5 Hz, 1 H, H-5), 4.46 (m, 1 H), 4.29 (d, J=8.6 Hz, 1 H, H-20a), 4.21 (d, J=1.6 Hz, 1 H), 4.10-4.07 (m, 2 H, H-20b and H-3), 2.51-2.34 (m, 3 H), 2.38 (s, 3 H, C H 3CO-), 2.56-2.20 (m, 2 H), 2.20 (s, 3 H, C H 3CO-), 2.10 (d, J=15.7 Hz, 1 H, H-6b), 1.91 (s, 3 H), 1.85 (s, 3 H ,-C H 3In C-18), 1.77 (s, 3 H), 1.77-1.65 (m, 2 H), 1.41-1.34 (m, 3 H), 1.25 (m, 6 H ,-C H 3 In C-16 and C-17), 1.00-0.97 (m, 6 H).
Methoxyl group-7-deoxidation-7 β, 8 β-methylene radical-10-acetoxyl group-Docetaxel (I-4a):
1H?NMR?(400?MHz,?CDCl 3)δ?8.14?(d,?J?=?7.4?Hz,?2?H,?Ph-H),?7.60?(t,?J?=?7.4?Hz,?1?H,?Ph-H),?7.50?(t,?J?=?7.8?Hz,?2?H,?Ph-H),?7.42-7.29?(m,?5?H,?Ph-H),?6.31?(brt,?J?=?8.6?Hz,?1?H,?H-13),?5.66?(d,?J?=?7.4?Hz,?1?H,?H-2),?5.37?(d,?J?=?9.4?Hz,?1?H,?CON H),?5.30?(brd,?1?H,?H-3′),?4.95?(s,?1?H,?H-10),?4.72?(d,?J?=?3.5?Hz,?1?H,?H-5),?4.60?(s,?1?H,?H-2′),?4.30?(d,?J?=?9.0?Hz,?1?H,?H-20a),?4.09?(d,?J?=?7.4?Hz,?1?H,?H-3),?4.04?(d,?J?=?8.6?Hz,?1?H,?H-20b),?3.45?(s,?3?H,?-O CH 3 ),?3.33?(brs,?1?H,?-OH),?2.43-2.29?(m,?3?H,?H-6a?and?H-14),?2.37?(s,?3?H,?C H 3CO?in?C-4),?2.26-2.18?(m,?1?H,?H-19a),?2.21?(s,?3?H,?C H 3CO?in?C-10),?2.10?(d,?J?=?16.0?Hz,?1?H,?H-6b),?1.86?(s,?3?H,?-C H 3?in?C-18),?1.63?(t?like,?1?H,?H-19b),?1.36-1.30?(m,?1?H,?H-7),?1.29?(s,?9?H,? Me 3C-),?1.27?(s,?3?H,?-C H 3 ),?1.23?(s,?3?H,?-C H 3 )；
7-deoxidation-7 β, 8 β-methylene radical-10-acetoxyl group-Docetaxel (I-4b):
1H?NMR?(400?MHz,?CDCl 3)δ?8.15?(d,?J?=?7.4?Hz,?2?H,?Ph-H),?7.60?(t,?J?=?7.4?Hz,?1?H,?Ph-H),?7.51?(t,?J?=?7.8?Hz,?2?H,?Ph-H),?7.42-7.31?(m,?5?H,?Ph-H),?6.29?(brt,?1?H,?H-13),?5.66?(d,?J?=?7.8?Hz,?1?H,?H-2),?5.41?(d,?J?=?9.4?Hz,?1?H,?CON H),?5.29?(brd,?1?H,?H-3′),?5.01?(s,?1?H,?H-10),?4.73?(d,?J?=?3.1?Hz,?1?H,?H-5),?4.61?(s,?1?H,?H-2′),?4.32?(d,?J?=?8.6?Hz,?1?H,?H-20a),?4.24?(s,?1?H),?4.13?(d,?J?=?7.4?Hz,?1?H,?H-3),?4.06?(d,?J?=?8.6?Hz,?1?H,?H-20b),?3.33?(brs,?1?H,?-OH),?2.44-2.31?(m,?3?H,?H-6a?and?H-14),?2.38?(s,?3?H,?C H 3CO?in?C-4),?2.24-2.20?(m,?1?H,?H-19a),?2.21?(s,?3?H,?C H 3CO?in?C-10),?2.13?(d,?J?=?16.0?Hz,?1?H,?H-6b),?1.85?(s,?3?H,?-C H 3?in?C-18),?1.77?(t?like,?1?H,?H-19b),?1.44?(m,?1?H,?H-7),?1.28?(s,?9?H,? Me 3C-),?1.26?(s,?3?H,?-C H 3 ),?1.20?(s,?3?H,?-C H 3 )。
The difluoroethylene base)-2-removes benzoyl-2-(-triazobenzene formyl radical)-7-deoxidation-7 β, 8 β-methylene radical-10-acetoxyl group-Docetaxel (I-5a):
1H?NMR?(400?MHz,?CDCl 3)δ?7.93?(d,?J?=?7.6?Hz,?1?H,?Ph-H),?7.87?(s,?J?=?7.4?Hz,?1?H,?Ph-H),?7.49?(t,?J?=?8.0?Hz,?1?H,?Ph-H),?7.23?(dd,?J?=?8.0,?1.6?Hz,?1?H,?Ph-H),?6.32?(s,?1H,?H-10),?6.25?(brt,?1?H,?H-13),?5.66?(d,?J?=?7.6?Hz,?1?H,?H-2),?4.90?(m,?2?H,?CON H?and?H-3′),?4.75?(d,?J?=?3.6?Hz,?1?H,?H-5),?4.56?(dd,?J?=?24.8,?8.0?Hz,?1?H,?CF 2C H),?4.37-4.33?(m,?2?H,?H-20a?and?H-2′),?4.26?(s,?1?H),?4.10?(d,?J?=?7.6?Hz,?1?H,?H-3),?4.03?(d,?J?=?8.4?Hz,?1?H,?H-20b),?3.45?(brs,?1?H),?2.88?(s,?1?H),?2.50-2.35?(m,?3?H,?H-6a?and?H-14),?2.39?(s,?3?H,?C H 3CO?in?C-4),?2.29-2.23?(m,?1?H,?H-19a),?2.20?(s,?3?H,?C H 3CO?in?C-10),?2.11?(d,?J?=?16.4?Hz,?1?H,?H-6b),?1.86?(s,?3?H,?-C H 3?in?C-18),?1.65?(t?like,?1?H,?H-19b),?1.40-1.35?(m,?1?H,?H-7),?1.26?(s,?9?H,? Me 3C-),?1.24?(s,?6?H,?-C H 3 )。
Remove tertbutyloxycarbonyl- 3'-N-((E)-2-butylene acyl group)-3'-(2,2-difluoroethylene base)-7-deoxidation-7 β, 8 β-methylene radical-10-acetoxyl group-Docetaxel (I-5b): 1H NMR (400 MHz, CDCl 3) δ 8.18 (d, J=7.2 Hz, 2 H, Ph-H), 7.60 (t, J=7.2 Hz, 1 H, Ph-H), 7.52 (t, J=7.2 Hz, 2 H, Ph-H), 6.72-6.63 (m, 1 H, CH 3C HCH), 6.32 (s, 1 H, H-10), 6.24 (brt, 1 H, H-13), 5.84 (d, J=8.8 Hz, 1 H, CH 3CHC H), 5.71-5.65 (m, 2 H), 5.21 (brt, J=9.4 Hz, 1 H, CON H), 4.73 (d, J=4.0 Hz, 1 H, H-5), 4.66 (ddd, J=24.8,10.0,1.6 Hz, 1 H), 4.34 (d, J=2.4 Hz, 1 H), 4.31 (d, J=8.8 Hz, 1 H, H-20a), 4.08 (d, J=6.8 Hz, 1 H, H-3), 4.07 (d, J=8.8 Hz, 1 H, H-20b), 2.87 (s, 1 H), 2.50-2.39 (m, 3 H, H-6a and H-14), 2.41 (s, 3 H, C H 3CO in C-4), and 2.25-2.18 (m, 1 H, H-19a), 2.20 (s, 3 H, C H 3CO in C-10), 2.10 (d, J=14.8 Hz, 1 H, H-6b), 1.85 (s, 3 H ,-C H 3In C-18), 1.73 (dd, J=7.2,1.6 Hz, 3 H, C H 3 CHC H), 1.68 (t like, 1 H, H-19b), 1.41-1.35 (m, 1 H, H-7), 1.26-1.23 (m, 6 H ,-C H 3 ).
Remove tertbutyloxycarbonyl- 3'-N-((E)-2-butylene acyl group)-3'-(2,2-difluoroethylene base)-2-removes benzoyl-2-(-triazobenzene formyl radical)-7-deoxidation-7 β, 8 β-methylene radical-10-acetoxyl group-Docetaxel (I-5c):
1H?NMR?(400?MHz,?CDCl 3)δ?7.93?(d,?J?=?7.6?Hz,?1?H,?Ph-H),?7.87?(s,?J?=?7.4?Hz,?1?H,?Ph-H),?7.50?(t,?J?=?8.0?Hz,?1?H,?Ph-H),?7.23?(dd,?J?=?8.0,?1.6?Hz,?1?H,?Ph-H),,?6.68-6.58?(m,?1?H,?CH 3C HCH),?6.32?(s,?1?H,?H-10),?6.21?(brt,?1?H,?H-13),?5.86?(d,?J?=?8.8?Hz,?1?H,?CH 3CHC H),?5.71?(d,?J?=?1.6?Hz,?1?H),?5.66?(d,?J?=?8.0?Hz,?2?H),?5.19?(brt,?J?=?9.2?Hz,?1?H,?CON H),?4.75?(d,?J?=?4.0?Hz,?1?H,?H-5),?4.65?(ddd,?J?=?24.4,?10.0,?1.6?Hz,?1?H),?4.37-4.32?(m,?3?H),?4.10-4.04?(m,?H-3?and?H-20b),?4.07?(d,?J?=?8.8?Hz,?1?H,?H-20b),?2.88?(s,?1?H),?2.52-2.39?(m,?3?H,?H-6a?and?H-14),?2.41?(s,?3?H,?C H 3CO?in?C-4),?2.30-2.22?(m,?1?H,?H-19a),?2.20?(s,?3?H,?C H 3CO?in?C-10),?2.11?(d,?J?=?16.4?Hz,?1?H,?H-6b),?1.85?(s,?3?H,?-C H 3?in?C-18),?1.74?(dd,?J?=?6.8,?1.6?Hz,?3?H,?C H 3 CHC H),?1.67?(dd,?J?=?7.2,?5.6?Hz,?1?H,?H-19b),?1.45-1.30?(m,?1?H,?H-7),?1.26-1.23?(m,?6?H,?-C H 3 )。
Remove tertbutyloxycarbonyl- 3'-N-((E)-4,4,4-three fluoro-2-butylene acyl groups)-3'-(2,2-difluoroethylene base)-7-deoxidation-7 β, 8 β-methylene radical-10-acetoxyl group-Docetaxel (I-5d): 1H NMR (400 MHz, CDCl 3) δ 8.20 (d, J=7.6 Hz, 2 H, Ph-H), 7.60 (t, J=7.2 Hz, 1 H, Ph-H), 7.52 (t, J=7.6 Hz, 2 H, Ph-H), 6.51-6.22 (m, 3 H, CF 3C HCH, CF 3CHC HAnd H-13), 6.32 (s, 1 H, H-10), 5.65 (d, J=7.6 Hz, 1 H), 5.31 (brt, J=9.4 Hz, 1 H, CON H), 4.73 (d, J=3.6 Hz, 1 H, H-5), 4.64 (dd, J=24.4,10.0,1 H), 4.35-4.31 (m, 3 H), 4.10-4.06 (m, 2 H), 3.56 (s, 1 H), 2.88 (s, 1 H), 2.52-2.43 (m, 3 H, H-6a and H-14), 2.41 (s, 3 H, C H 3CO in C-4), 2.29-2.09 (m, 2 H), 2.20 (s, 3 H, C H 3CO in C-10), 1.86 (s, 3 H ,-C H 3In C-18), 1.68 (t like, 1 H, H-19b), 1.47-1.37 (m, 1 H, H-7), 1.27-1.23 (m, 6 H ,-C H 3 ).
Remove tertbutyloxycarbonyl- 3'-N-((E)-4,4,4-three fluoro-2-butylene acyl groups)-3'-(2,2-difluoroethylene base)-2-removes benzoyl-2-(-triazobenzene formyl radical)-7-deoxidation-7 β, 8 β-methylene radical-10-acetoxyl group-Docetaxel (I-5e): 1H NMR (400 MHz, CDCl 3) δ 7.96 (d, J=7.9 Hz, 1 H, Ph-H), 7.90 (d, J=1.6 Hz, 1 H, Ph-H), 7.50 (t, J=7.9 Hz, 1 H, Ph-H), 7.23 (dd, J=7.9,1.6 Hz, 1 H, Ph-H), (6.44-6.38 m, 2 H), 6.32 (s, 1 H, H-10), 6.23 (brt, 1 H, H-13), 5.65 (d, J=7.9 Hz, 1 H), 5.31 (brt, J=9.5 Hz, 1 H, CON H), 4.75 (d, J=4.0 Hz, 1 H, H-5), 4.64 (dd, J=24.4,10.0,1 H), 4.37-4.34 (m, 3 H), 4.09-4.04 (m, 2 H), 2.89 (s, 1 H), 2.50-2.31 (m, 3 H, H-6a and H-14), 2.42 (s, 3 H, C H 3CO in C-4), 2.24-2.09 (m, 2 H), 2.20 (s, 3 H, C H 3CO in C-10), 1.85 (s, 3 H ,-C H 3In C-18), 1.66 (t like, 1 H, H-19b), 1.41-1.30 (m, 1 H, H-7), 1.27-1.23 (m, 6 H ,-C H 3 ).
Final synthetic part Taxane derivative has carried out the anti tumor activity in vitro evaluation experimental to KB (strain of human oral squamous cell carcinoma), KB/VCR (the human oral squama cancer drug-resistant cell strain of anti-vincristine(VCR)), MCF-7 (human breast cancer cell strain), MCF-7/ADR (the human breast carcinoma drug-resistant cell strain of adriamycin-resistant), and activity test method is as follows:
1. experiment material: KB, KB/VCR, four kinds of cell strains of MCF-7, MCF-7/ADR are Shanghai medicine institute of Chinese Academy of Sciences pharmacological evaluation chamber provides; Sodium.alpha.-ketopropionate, glutamine, sulphonyl rhodamine B (sulforhodamin B, SRB), dimethyl sulfoxide (DMSO) (DMSO) (being U.S. Sigma company product); Calf serum (FBS), DMEM substratum, MEM culture medium dry powder and trypsin are U.S. GIBCO company product); Other reagent such as trichoroacetic acid(TCA), acetic acid are analytical pure (Chemical Reagent Co., Ltd., Sinopharm Group); Water is injection physiological saline.
2. cell cultures: KB and KB/VCR cell cultures nutrient solution component are: MEM+ glutamine (1%)+Sodium.alpha.-ketopropionate (1%)+calf serum (10%); MCF-7 cell cultures nutrient solution component is: DMEM+ calf serum (10%); MCF-7/ADR cell cultures nutrient solution component is: MEM+ Regular Insulin (1%)+Sodium.alpha.-ketopropionate (1%)+calf serum (10%).All cells is incubated at 5% CO 2, in the incubator of 37 ℃ of saturated humidities;
3.SRB method: take the logarithm KB in vegetative period, KB/VCR, four kinds of cell strains of MCF-7, MCF-7/ADR, with 0.125% trysinization, blow and spare into single cell suspension, living cell counting.KB, KB/VCR, MCF-7, MCF-7/ADR cell are respectively with 6 ~ 7 * 10 3, 4 ~ 5 * 10 3, 4 ~ 5 * 10 3, 7 ~ 8 * 10 3Individual cells/well is inoculated in (every hole 100 μ L) in 96 orifice plates.Behind cell cultures 24 h, the every hole of experimental group adds in advance the compound of 8 gradient concentrations that prepare with physiological saline, and parallel survey is three groups under every kind of medicine same concentrations.After cultivating 72 h, every hole adds 10% Tricholroacetic Acid (TCA, 100 μ L) of 4 ℃ of precoolings, places 1 h fixed cells at 4 ℃.Then with deionized water wash 6 ~ 8 times of each hole of culture plate, 37 ℃ are dried to the wet trace of nothing in electric drying oven with forced convection.Every then hole adds 0.4% SRB (the acetic acid preparation with 1%), 100 μ L, lucifuge 15 min that dye under the room temperature.Discard in each hole behind the liquid, acetic acid washing with 1% 6 ~ 8 times, be dried to the wet trace of nothing then under 37 ℃ in electric drying oven with forced convection after, Tris (150 μ L/ hole) the dissolving SRB that every hole adds 10 mmol/L measures OD value and calculation of half inhibitory concentration IC with microplate reader with the wavelength of 515 nm 50Value.Cell proliferation inhibition rate is calculated as follows: cell proliferation inhibition rate (%)=(1-experimental group OD value)/control group OD value) * 100, every kind of compound three batch totals are calculated the gained inhibiting rate average.Repeat aforesaid operations once, with twice gained half-inhibition concentration IC 50Value is averaged, and test result is summarized as follows shown in the table:
? KB (nM) KB/VCR (nM) R/S MCF-7 (nM) MCF-7/ADR (nM) R/S
Zorubicin NT NT — 32.4 7.6 (μM) 233.4
Vincristine(VCR) 11.1 588.0 53.0 NT NT —
Taxol 10.3 4.0 (μM) 388.3 9.6 >100.0 (μM) >10000
Docetaxel 7.3 169.7 23.2 1.7 1530.5 900.3
Larotaxel 15.8 57.5 3.6 18.6 280.8 15.1
Ⅰ-1a 30.4 167.1 5.5 71.0 667.9 9.4
Ⅰ-1b 13.7 63.0 4.7 37.4 223.2 6.0
Ⅰ-1c 37.2 237.6 6.4 91.8 670.3 7.3
Ⅰ-1d 17.5 93.0 5.3 35.1 231.5 6.6
Ⅰ-1e 20.9 81.0 3.9 26.7 239.8 9.0
Ⅰ-1f 18.2 50.3 2.8 28.7 175.6 6.1
Ⅰ-1g 25.7 125.6 4.9 20.5 449.6 21.9
Ⅰ-1h 11.8 42.0 3.6 23.8 56.9 2.4
Ⅰ-2b 2.5 14.2 5.7 1.6 10.6 6.6
Ⅰ-3a 13.6 41.4 3.0 6.1 48.1 7.9
Ⅰ-3c 3.2 19.4 6.1 2.4 14.8 6.2
Ⅰ-3b 0.038 10.7 281.6 0.039 9.2 236.7
Ⅰ-2c 59.2 103.3 1.7 79.7 169.3 2.1
Ⅰ-3d 15.4 95.6 6.2 13.5 308.1 22.8
Ⅰ-3f 0.1 12.2 122.0 0.24 45.5 189.6
Ⅰ-3e 0.6 23.3 38.3 1.7 138.7 81.6
Ⅰ-2a 3.0 8.1 2.7 2.8 25.6 9.1
Ⅰ-4a 3.2 65.9 20.6 9.0 269.9 30.0
Ⅰ-4b 2.4 22.5 9.4 7.2 165.8 12.3
Ⅰ-5a 6.1 22.9 3.8 35.9 56.6 1.6
Ⅰ-5b 2.5 25.8 10.3 1.4 417.6 298.3
Ⅰ-5c 5.3 15.2 2.9 6.0 37.1 6.2
Ⅰ-5d 4.7 298.0 64.3 22.7 4.7 (μM) 205.2
Ⅰ-5e 10.5 95.4 9.1 24.6 394.4 16.0
From the biological activity test result as can be seen, this compounds majority of compound can suppress the growth of tumour cell effectively, especially at multidrug resistance (MDR) tumour cell (MCF-7/ADR, KB/VCR), and 9 shown compounds I-1h, I-2a, I-2b, I-3a, I-3b, I-3c, I-3f, I-5a, I-5cWith taxol (Paclitaxel, Taxol) compare and have 3 ~ 5 active raisings of the order of magnitude, with Docetaxel (Docetaxel, Taxotere) compare and have 1 ~ 3 active raising of the order of magnitude, with La Luotasai (Larotaxel XRP9881) compares and has 1 ~ 2 active raising of the order of magnitude, thereby, this taxane derivatives can be used for clinically multidrug resistance tumor treatment and the exploitation to high expression level P-glycoprotein, prolongs the survival time of late tumor patient.

Claims (14)

1. a class has the taxane derivatives of structure shown in the following general formula (I):
Wherein:
R 1Representative-C (O) OR 6,-C (O) Ar ,-C (O) CH=CR 7R 8
R 2Representative-Ar, alkyl ,-CH=CR 7R 8
R 3Represent hydrogen atom, alkyl, alkoxyl group, halogen, cyano group, azido-, fluorine substituted alkyl, fluorine substituted alkoxy;
R 4Represent hydrogen atom ,-C (O) R 9Maybe can increase water miscible hydroxyl substituent, R 9Represent C 1～C 10Straight chain or have alkyl or cycloalkyl, the aryl of side chain;
R 5Represent hydrogen atom, silicon ether, ester group maybe can increase water miscible hydroxyl substituent;
R 6Represent C 3～C 10The alkyl of straight or branched;
R 7, R 8Represent identical or different C 1～C 10Straight chain or have the C that the alkyl, cycloalkyl, halogen, halogen of side chain replace 1～C 10Straight chain or have the alkyl or cycloalkyl of side chain.
2. taxane derivatives with structure shown in the following general formula (IV):
Figure DEST_PATH_FDA0000067832530000012
Wherein:
R 1Representative-C (O) OR 6,-C (O) Ar ,-C (O) CH=CR 7R 8
R 2Representative-Ar, alkyl ,-CH=CR 7R 8
R 3Represent hydrogen atom, alkyl, alkoxyl group, halogen, cyano group, azido-, fluorine substituted alkyl, fluorine substituted alkoxy;
R 4Represent hydrogen atom ,-C (O) R 9Maybe can increase water miscible hydroxyl substituent, R 9Represent C 1～C 10Straight chain or have alkyl or cycloalkyl, the aryl of side chain;
R 6Represent C 3～C 10The alkyl of straight or branched;
R 7, R 8Represent identical or different C 1～～C 10Straight chain or have the C that the alkyl, cycloalkyl, halogen, halogen of side chain replace 1～C 10Straight chain or have the alkyl or cycloalkyl of side chain.
3. taxane derivatives according to claim 1 and 2, wherein, R 1For :-C (O) CH=CF 2,-C (O) OCCH 3,-C (O) CH=C (CH 3) 2,-C (O) CH=CHCH 3,-C (O) CH=CHCF 3
4. taxane derivatives according to claim 1 and 2, wherein, R 2Be C 1～C 10Straight chain or have alkyl, the cycloalkyl of side chain.
5. taxane derivatives according to claim 1 and 2, wherein, R 2For :-CH=CF 2,-CH=C (CH 3) 2,-CH 2CH (CH 3) 2
6. taxane derivatives according to claim 1, wherein, R 3For methyl, chlorine, fluorine, methoxyl group ,-CF 3,-CHF 2,-CF 2CF 3,-OCF 3,-OCHF 2,-OCF 2CF 3
7. taxane derivatives according to claim 1 and 2, wherein, described can the water miscible hydroxyl substituent of increase be C 5～C 12Carbohydrate or-CO-X-Y, wherein X representative-(CH 2) n-or-CH=CH-, n=1～6; Y representation carboxy and pharmaceutically acceptable various salt thereof, sulfonic group and pharmaceutically acceptable various salt thereof ,-NR 10R 11And pharmaceutically acceptable various salt, C 5～C 12Carbohydrate, wherein, R 10, R 11Represent identical or different C 1～C 10Straight chain or have alkyl, cycloalkyl of side chain etc., X and Y also can represent C 5～C 12Carbohydrate.
8. taxane derivatives according to claim 1 and 2, wherein, R 6Be the tertiary butyl, isobutyl-, isopentyl.
9. method for preparing claim 1 or 2 described taxane derivatives, described method comprises the steps:
The series compound that is prepared by general formula (II) is through the suitably activation of condensing agent, under suitable solvent action, react with the compound shown in general formula (III-1), (III-2), (III-3), (III-4), obtain the product shown in the general formula (I), remove R then 5Protecting group obtains the taxane derivatives shown in the logical formula IV:
Figure DEST_PATH_FDA0000067832530000031
R in the formula 1, R 2, R 3, R 4, R 5Definition identical with claim 1～2.
10. the method for preparing taxane derivatives according to claim 9; it is characterized in that compound shown in the general formula (II) can be by leading to the compound shown in the formula V and docking as beta-lactam, five yuan of oxazolidine carboxylic-acids, straight-chain carboxylic acid's class side chains; remove protecting group then and prepare R 3, R 4Definition identical with claim 1～2:
Figure DEST_PATH_FDA0000067832530000041
11. the method for preparing taxane derivatives according to claim 10; when described side chain is beta-lactam (VI-1); the following acquisition of compound shown in the general formula (II): the compound shown in the logical formula V docks with beta-lactam side chain (VI-1); obtain the intermediate shown in the general formula (II-1); remove the side chain amino protecting group then, R 2, R 3, R 4, R 5Definition identical with claim 1～2; The pendant hydroxyl group protecting group that perhaps removes the intermediate shown in the general formula (II-1) earlier obtains the intermediate shown in the general formula (II-2), removes the side chain amino protecting group again and prepares compound shown in the general formula (II-3), R 2, R 3, R 4Definition identical with claim 1～2:
Figure DEST_PATH_FDA0000067832530000042
12. the method for preparing taxane derivatives according to claim 10 is characterized in that the compound shown in the logical formula V prepares (Scheme 2) by following reaction formula:
Figure DEST_PATH_FDA0000067832530000051
R in the formula 3, R 4Definition and claim 1～2 in identical.
13. the purposes of the described taxane derivatives of claim 1 aspect the preparation antitumor drug.
14. the purposes of the described taxane derivatives of claim 1 aspect the preparation medicine, described medicine is used for the treatment of the tumour to the multidrug resistance chemotherapy of tumors failure of high expression level P-glycoprotein.
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CN109485593A (en) * 2018-12-12 2019-03-19 福建紫杉园生物有限公司 A kind of synthesis technology of La Luotasai chiral side chain
WO2024094110A1 (en) * 2022-11-03 2024-05-10 北京诺康达医药科技股份有限公司 Tm2 compound crystal form, preparation method therefor, and use thereof

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CN109485593A (en) * 2018-12-12 2019-03-19 福建紫杉园生物有限公司 A kind of synthesis technology of La Luotasai chiral side chain
WO2024094110A1 (en) * 2022-11-03 2024-05-10 北京诺康达医药科技股份有限公司 Tm2 compound crystal form, preparation method therefor, and use thereof

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